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29 results on '"MESH: Antineoplastic Agents, Alkylating"'

1. Radiation guidelines for gliomas

Author

Antoni, D., Feuvret, L., Biau, J., Robert, C., Mazeron, J.-J., Noël, G., Imagerie Moléculaire et Stratégies Théranostiques (IMoST), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)

Subjects
Organs at Risk, Recommandations, MESH: Neoplasm Grading, Recommendations, MESH: Antineoplastic Agents, Alkylating, Radiation Tolerance, MESH: Magnetic Resonance Imaging, MESH: Glioma, Gliome anaplasique, Societies, Medical, MESH: Aged, MESH: Middle Aged, MESH: Organs at Risk, MESH: Radiation Tolerance, Brain Neoplasms, MESH: Glioblastoma, MESH: Clinical Decision-Making, Age Factors, Glioma, Middle Aged, MESH: Radiation Oncology, Magnetic Resonance Imaging, Radiation therapy, Oncology, Diffuse glioma, MESH: Brain Neoplasms, MESH: Biomarkers, Tumor, France, MESH: Karnofsky Performance Status, Gliome diffus, Glioblastome, MESH: Societies, Medical, Clinical Decision-Making, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, Temozolomide, Humans, Radiology, Nuclear Medicine and imaging, Karnofsky Performance Status, MESH: Temozolomide, Antineoplastic Agents, Alkylating, Radiothérapie, Aged, MESH: Age Factors, French society for radiation oncology, MESH: Humans, Biologie moléculaire, MESH: France, Radiation Oncology, Neoplasm Grading, Glioblastoma, Anaplastic glioma, Biomarkers, Société française de radiothérapie oncologique
Abstract

International audience; Gliomas are the most frequent primary brain tumour. The proximity of organs at risk, the infiltrating nature, and the radioresistance of gliomas have to be taken into account in the choice of prescribed dose and technique of radiotherapy. The management of glioma patients is based on clinical factors (age, KPS) and tumour characteristics (histology, molecular biology, tumour location), and strongly depends on available and associated treatments, such as surgery, radiation therapy, and chemotherapy. The knowledge of molecular biomarkers is currently essential, they are increasingly evolving as additional factors that facilitate diagnostics and therapeutic decision-making. We present the update of the recommendations of the French society for radiation oncology on the indications and the technical procedures for performing radiation therapy in patients with gliomas.

Published
2021

2. Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in Refractory or Relapsed T-Cell Lymphomas: The BENTLY Trial

Author

Arnaud Jaccard, Momar Diouf, Gandhi Damaj, Thierry Lamy, Pascale Cony-Makhoul, Krimo Bouabdallah, Bertrand Joly, Roch Houot, Guillaume Cartron, Steven Le Gouill, Emmanuel Gyan, Remy Gressin, Jean-Pierre Vilque, Bachra Choufi, Marie-Christine Béné, Sophie Park, Michael Bubenheim, Laurence Sanhes, Aline Schmidt-Tanguy, Laurent Voillat, Jean-Marc Schiano-de Collela, Anne Banos, Alain Saad, Olivier Tournilhac, Jean-Pierre Marolleau, Antoine Martin, CHU Amiens-Picardie, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Duchenne, CH Boulogne sur Mer, CIC - Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Bayonne, Centre Hospitalier de la Côte Basque (CHCB), CHU Limoges, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Chalon-sur-Saône William Morey, Hôpital Sud-Fancilien, CH Sud-Fancilien, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital de Béziers, CH Béziers, Centre Hospitalier d'Annecy, Centre hospitalier d'Annecy, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital de Perpignan, Centre Hospitalier Saint Jean de Perpignan, CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Avicenne [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), CH de la Côte Basque, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and Le Corre, Morgane

Subjects
Male, MESH: Remission Induction, Cancer Research, medicine.medical_treatment, Salvage therapy, MESH: Antineoplastic Agents, Alkylating, Gastroenterology, MESH: Aged, 80 and over, 0302 clinical medicine, Bendamustine Hydrochloride, Prospective Studies, Aged, 80 and over, MESH: Aged, education.field_of_study, MESH: Middle Aged, Remission Induction, MESH: Neoplasm Staging, MESH: Follow-Up Studies, Middle Aged, MESH: Lymphoma, T-Cell, Peripheral, Prognosis, MESH: Drug Resistance, Neoplasm, MESH: Lymphoma, T-Cell, Cutaneous, Lymphoma, T-Cell, Cutaneous, MESH: Salvage Therapy, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Nitrogen Mustard Compounds, Female, MESH: Neoplasm Recurrence, Local, medicine.drug, Adult, Bendamustine, medicine.medical_specialty, MESH: Survival Rate, Population, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Neutropenia, MESH: Prognosis, 03 medical and health sciences, Refractory, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Antineoplastic Agents, Alkylating, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Survival rate, Aged, Neoplasm Staging, Salvage Therapy, Chemotherapy, MESH: Humans, business.industry, MESH: Nitrogen Mustard Compounds, Lymphoma, T-Cell, Peripheral, MESH: Adult, medicine.disease, MESH: Male, MESH: Prospective Studies, Lymphoma, Surgery, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local, business, MESH: Female, Follow-Up Studies, 030215 immunology
Abstract

Purpose To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. Patients and Methods Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m2 per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). Conclusion Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.

Published
2013

3. A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas

Author

George D. Demetri, Andres Poveda, Federica Grosso, Jaap Verweij, Vicente Alfaro, Jean-Yves Blay, Patrick Schöffski, Antonio Nieto, Paolo G. Casali, Robert G. Maki, Axel Le Cesne, Pilar Lardelli, Carme Balaña, Sara Cresta, Institut Gustave Roussy (IGR), Istituto Nazionale dei Tumori di Milano, Fondazione IRCCS, Sarcoma program, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Pediatric Allergy and Pneumology Unit, Children's Hospital La Fe, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], and Medical Oncology

Subjects
Oncology, Male, Cancer Research, Pathology, Time Factors, Kaplan-Meier Estimate, MESH: Antineoplastic Agents, Alkylating, Translocation, Genetic, MESH: Tetrahydroisoquinolines, 0302 clinical medicine, Tetrahydroisoquinolines, Alveolar soft part sarcoma, MESH: Dioxoles, Trabectedin, MESH: Treatment Outcome, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Sarcoma, Middle Aged, Synovial sarcoma, MESH: Translocation, Genetic, 3. Good health, Treatment Outcome, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, Clear-cell sarcoma, MESH: Clinical Trials, Phase II as Topic, medicine.drug, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dioxoles, Biology, Disease-Free Survival, 03 medical and health sciences, Young Adult, Clinical Trials, Phase II as Topic, Internal medicine, medicine, Humans, Doxorubicin, Survival rate, Antineoplastic Agents, Alkylating, MESH: Kaplan-Meier Estimate, 030304 developmental biology, Aged, Retrospective Studies, MESH: Adolescent, Endometrial stromal sarcoma, MESH: Humans, MESH: Time Factors, MESH: Adult, MESH: Retrospective Studies, medicine.disease, MESH: Male, MESH: Sarcoma, MESH: Disease-Free Survival, MESH: Female
Abstract

International audience; AIMS: Approximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. METHODS: The current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. RESULTS: TRS subtypes were: synovial sarcoma (SS, n=45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n=27), alveolar soft part sarcoma (ASPS, n=4), endometrial stromal sarcoma (ESS, n=3) and clear cell sarcoma (CCS, n=2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1-48; median dose intensity=0.40 mg/m(2)/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR=10%; 95% CI, 4-19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48-70%). Median PFS was 4.1 months (6-month PFS rate=40%). Median overall survival was 17.4 months (survival rate at 12 months=60%). Trabectedin had a manageable safety profile. CONCLUSION: Trabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS.

Published
2012

4. A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials

Author

Robert G. Maki, Juhui James Jiao, Jean-Yves Blay, Jean-Louis Misset, A. Yovine, Antonio Nieto, Axel Le Cesne, Pilar Frontelo, Suzette Delaloge, George D. Demetri, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'Oncologie Médicale, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sarcoma program, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Centre des maladies du sein, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), PharmaMar Medical, Pharma Mar Medical R&D, Pediatric Allergy and Pneumology Unit, Children's Hospital La Fe, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, medicine.medical_treatment, Phases of clinical research, MESH: Antineoplastic Agents, Alkylating, Rhabdomyolysis, MESH: Tetrahydroisoquinolines, MESH: Aged, 80 and over, 0302 clinical medicine, Neoplasms, Tetrahydroisoquinolines, MESH: Child, MESH: Neoplasms, MESH: Dioxoles, Pharmacology (medical), Child, Trabectedin, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Incidence (epidemiology), Alanine Transaminase, Middle Aged, 3. Good health, Oncology, MESH: Young Adult, 030220 oncology & carcinogenesis, Anesthesia, Vomiting, Female, medicine.symptom, medicine.drug, Adult, medicine.medical_specialty, Neutropenia, Adolescent, MESH: Neutropenia, Nausea, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dioxoles, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Adverse effect, Antineoplastic Agents, Alkylating, Aged, 030304 developmental biology, MESH: Adolescent, Pharmacology, Chemotherapy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Rhabdomyolysis, MESH: Male, MESH: Alanine Transaminase, business, MESH: Female
Abstract

International audience; PURPOSE: To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. METHODS: This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and April 2008. Trabectedin was administered intravenously as 1 of 3 schedules: 24-hour infusion every 3 weeks (q3wk 24-h; n = 570/2,818 cycles), 3-hour infusion every 3 weeks (q3wk 3-h; n = 258/1,003 cycles), and 3-hour infusion for three consecutive weeks every 4 weeks (qwk 3-h; n = 304/1,198 cycles). RESULTS: The majority of patients (90%) had received previous chemotherapy. Patients were given a median of three treatment cycles of trabectedin (range, 1-59). Nausea, fatigue and vomiting were the most common trabectedin-related adverse events, reported in ≥20% of patients. Reversible myelosuppression (mainly neutropenia) and transient reversible transaminase increases were the most common laboratory abnormalities seen with trabectedin, with a very low incidence of relevant clinical consequences. Deaths associated with drug-related adverse events were infrequent, occurring in 19 (1.7%) patients. CONCLUSION: Single-agent trabectedin treatment was reasonably well tolerated. Trabectedin can be administered for prolonged periods to patients with sustained clinical benefit (induction of disease stability or shrinkage) without cumulative toxicities over time.

Published
2011

5. Analysis of MGMT methylation with the therascreen® MGMT Pyro® Kit (Qiagen). A method verification

Author

Jean-Luc Prétet, Séverine Valmary-Degano, David Guenat, Gabriel Viennet, Sandrine Magnin, Christiane Mougin, Alexandra Luquain, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
MESH: Sequence Analysis, DNA, Methyltransferase, MESH: Reagent Kits, Diagnostic, MESH: Accreditation, MESH: Monitoring, Physiologic, MESH: Molecular Diagnostic Techniques, MESH: Antineoplastic Agents, Alkylating, Accreditation, MESH: DNA Methylation, Promoter Regions, Genetic, DNA Modification Methylases, MESH: DNA Modification Methylases, MESH: Treatment Outcome, Genetics, Brain Neoplasms, MESH: Glioblastoma, General Medicine, Methylation, Repeatability, Prognosis, 3. Good health, Dacarbazine, MESH: Reproducibility of Results, Treatment Outcome, pyrosequencing, MESH: DNA Repair Enzymes, Molecular Diagnostic Techniques, DNA methylation, MESH: Brain Neoplasms, on-site verification, MESH: Biomarkers, Tumor, MGMT, medicine.drug, ISO 15189, Coefficient of variation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Dacarbazine, MESH: Prognosis, MESH: Promoter Regions, Genetic, medicine, Biomarkers, Tumor, Temozolomide, Humans, MESH: Tumor Suppressor Proteins, Antineoplastic Agents, Alkylating, MESH: Temozolomide, Monitoring, Physiologic, Detection limit, Reproducibility, MESH: Humans, business.industry, Tumor Suppressor Proteins, Reproducibility of Results, Sequence Analysis, DNA, DNA Methylation, Molecular biology, DNA Repair Enzymes, Reagent Kits, Diagnostic, methylation, business, Glioblastoma, validation method
Abstract

International audience; Promoter methylation of the MGMT gene, encoding the enzyme O6-methylguanine-ubiquitous methyltransferase, is a theranostic good prognosis marker of glioblastomas treated with alkylating chemotherapy (temozolomide, Temodal(®)). Among the methylation analysis techniques, pyrosequencing is a reproducible and sensitive quantitative method. As part of the accreditation of the hospital platform of molecular genetics of cancer, Besançon, our objective was to verify the performance of the pyrosequencing commercial kit therascreen(®) MGMT Pyro(®) (Qiagen) in terms of repeatability, reproducibility, limit of blank (LOB), limit of detection (LOD), linearity and contamination by the guide SH GTA 04 delivered by the Cofrac. The repeatability tests show an average methylation of 3.22% [standard deviation (SD) = 0.41, coefficient of variation (CV) = 12.75%] for the unmethylated control and 70.16% (SD = 2.20, CV = 3.14%) for the methylated control. Reproducibility demontrates an average methylation of 1.39% (SD = 0.25, CV = 18.25%) for the unmethylated control and of 94.03% (SD = 2.56, CV = 2.73%) for the methylated control. The percentages of LOB and LOD are respectively 3.43% and 6.22% methylation. The regression coefficient of 0,983 confirms the linearity of the assay from 0% to 100% methylation. No contamination has been observed. Over 40% of glioblastomas studied in 2013 in our laboratory have shown a methylated MGMT gene. Our results confirms that the theraScreen(®) MGMT Pyro(®) kit (Qiagen) is performant in compliance with the quality requirements of the NF EN ISO 15189 for the routine analysis of methylation status of MGMT in glioblastomas.

Published
2015

6. Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide

Author

Roberto Pallini, Roberta Calabrese, Federica Pelacchi, Alessia Muzi, Lucia Ricci-Vitiani, Daniele Runci, Lucio Tentori, Grazia Graziani, Fabio Ciccarone, Paola Caiafa, Department of System Medicine, Università degli Studi di Roma Tor Vergata [Roma], Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Institute of Neurosurgery, Università cattolica del Sacro Cuore [Roma] (Unicatt), This work was supported by a grant from 'Associazione Italiana per la Ricercasul Cancro' (AIRC, Investigator Grant IG 2013 N. 4042 to G.G. and Start-up6326 to L.R.V.), International FIRB 2006 grant (RBIN06E9Z8_003) to P.C., and 'Fondid’Ateneo, Linea D1, Università Cattolica del Sacro Cuore' and 'ProgrammaOncotecnologico 2010' to R.P.

Subjects
Cancer Research, Settore MED/27 - NEUROCHIRURGIA, Poly (ADP-Ribose) Polymerase-1, MESH: Antineoplastic Agents, Alkylating, Poly (ADP-Ribose) Polymerase Inhibitor, O6-methylguanine-DNA-methyltransferase, 0302 clinical medicine, MESH: DNA Methylation, Neoplasm, Promoter Regions, Genetic, MESH: CpG Islands, Temozolomide, PARP inhibitor, Cancer stem cells, O6-methylguanine-DNA-methyltransferase,Chemoresistance, 0303 health sciences, Cancer stem cells, MESH: Glioblastoma, Settore BIO/14, MESH: Drug Resistance, Neoplasm, 3. Good health, Dacarbazine, Oncology, 030220 oncology & carcinogenesis, PARP inhibitor, Neoplastic Stem Cells, Poly(ADP-ribose) Polymerases, Chemoresistance, Research Article, medicine.drug, MESH: Cell Line, Tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Biology, MESH: Dacarbazine, O(6)-Methylguanine-DNA Methyltransferase, 03 medical and health sciences, Cancer stem cell, Cell Line, Tumor, MESH: Promoter Regions, Genetic, Temozolomide, medicine, Genetics, Humans, PTEN, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antineoplastic Agents, Alkylating, 030304 developmental biology, MESH: Humans, MESH: O(6)-Methylguanine-DNA Methyltransferase, MESH: Poly(ADP-ribose) Polymerases, O-6-methylguanine-DNA methyltransferase, DNA Methylation, medicine.disease, MESH: Neoplastic Stem Cells, Poly(ADP-ribose) polymerase-1, Drug Resistance, Neoplasm, Cancer research, biology.protein, CpG Islands, Glioblastoma
Abstract

Background Chemoresistance of glioblastoma multiforme (GBM) has been attributed to the presence within the tumor of cancer stem cells (GSCs). The standard therapy for GBM consists of surgery followed by radiotherapy and the chemotherapeutic agent temozolomide (TMZ). However, TMZ efficacy is limited by O6-methylguanine-DNA-methyltransferase (MGMT) and Mismatch Repair (MMR) functions. Strategies to counteract TMZ resistance include its combination with poly(ADP-ribose) polymerase inhibitors (PARPi), which hamper the repair of N-methylpurines. PARPi are also investigated as monotherapy for tumors with deficiency of homologous recombination (HR). We have investigated whether PARPi may restore GSC sensitivity to TMZ or may be effective as monotherapy. Methods Ten human GSC lines were assayed for MMR proteins, MGMT and PARP-1 expression/activity, MGMT promoter methylation and sensitivity to TMZ or PARPi, alone and in combination. Since PTEN defects are frequently detected in GBM and may cause HR dysfunction, PTEN expression was also analyzed. The statistical analysis of the differences in drug sensitivity among the cell lines was performed using the ANOVA and Bonferroni’s post-test or the non-parametric Kruskal-Wallis analysis and Dunn’s post-test for multiple comparisons. Synergism between TMZ and PARPi was analyzed by the median-effect method of Chou and Talalay. Correlation analyses were done using the Spearman’s rank test. Results All GSCs were MMR-proficient and resistance to TMZ was mainly associated with high MGMT activity or low proliferation rate. MGMT promoter hypermethylation of GSCs correlated both with low MGMT activity/expression (Spearman’s test, P = 0.004 and P = 0.01) and with longer overall survival of GBM patients (P = 0.02). Sensitivity of each GSC line to PARPi as single agent did not correlate with PARP-1 or PTEN expression. Notably, PARPi and TMZ combination exerted synergistic antitumor effects in eight out of ten GSC lines and the TMZ dose reduction achieved significantly correlated with the sensitivity of each cell line to PARPi as single agent (P = 0.01). Conclusions The combination of TMZ with PARPi may represent a valuable strategy to reverse GSC chemoresistance.

Published
2014

7. Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth

Author

Grégoire Mignot, Alice Hervieu, Cédric Rébé, Lionel Apetoh, Frédérique Végran, Fanny Chalmin, François Ghiringhelli, Mélanie Bruchard, Pierre Vabres, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), CHU Dijon, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Mignot, Grégoire, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Laboratoire Electronique, Informatique et Image ( Le2i ), and Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Skin Neoplasms, Melanoma, Experimental, CD8-Positive T-Lymphocytes, Pharmacology, MESH: Antineoplastic Agents, Alkylating, Ligands, Biochemistry, Mice, Interleukin 21, 0302 clinical medicine, MESH: Up-Regulation, MESH: Ligands, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Up-Regulation, MESH : Ligands, MESH : Melanoma, Experimental, Melanoma, MESH : Mice, Nude, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, Up-Regulation, 3. Good health, Dacarbazine, Killer Cells, Natural, MESH: Melanoma, Experimental, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, MESH: NK Cell Lectin-Like Receptor Subfamily K, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Killer Cells, Natural, medicine.drug, MESH: Killer Cells, Natural, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon-gamma, MESH : Antineoplastic Agents, Alkylating, Mice, Nude, MESH : Mice, Inbred C57BL, Dermatology, Biology, Major histocompatibility complex, MESH: Dacarbazine, Interferon-gamma, 03 medical and health sciences, Immune system, Downregulation and upregulation, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH : Mice, medicine, MESH : NK Cell Lectin-Like Receptor Subfamily K, MESH: Mice, Nude, Animals, Humans, MESH : Dacarbazine, Antineoplastic Agents, Alkylating, Molecular Biology, MESH: Mice, MESH : Interferon-gamma, MESH: Humans, MESH : Cell Line, Tumor, MESH: Skin Neoplasms, MESH : Skin Neoplasms, MESH : Humans, Cell Biology, medicine.disease, MESH : Disease Models, Animal, Mice, Inbred C57BL, Disease Models, Animal, biology.protein, MESH : Animals, MESH: Disease Models, Animal, CD8, 030215 immunology
Abstract

International audience; Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo.

Published
2013

8. [Cardiotoxicity of chemotherapies]

Author

Marion, Castel, Fabien, Despas, Anouchka, Modesto, Céline, Gales, Benjamin, Honton, Michel, Galinier, Jean-Michel, Senard, Atul, Pathak, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de pharmacologie médicale et clinique, CHU Toulouse [Toulouse], Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Simon, Marie Francoise, Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Cardiologie [CHU Toulouse], and Pôle Cardiovasculaire et Métabolique [CHU Toulouse]

Subjects
Heart Failure, MESH: Humans, Drug-Related Side Effects and Adverse Reactions, Heart Diseases, MESH: Heart Diseases, MESH: Taxoids, Myocardial Ischemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Antineoplastic Agents, Alkylating, Antibodies, Monoclonal, Humanized, MESH: Drug Toxicity, MESH: Antineoplastic Combined Chemotherapy Protocols, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, MESH: Heart Failure, MESH: Molecular Targeted Therapy, Humans, MESH: Myocardial Ischemia, MESH: Protein Kinase Inhibitors, Taxoids, Molecular Targeted Therapy, Antineoplastic Agents, Alkylating, Protein Kinase Inhibitors
Abstract

International audience; The spectrum of chemotherapy's cardiac side effect of chemotherapy has expanded with the new combinations of cytotoxic and targeted therapies over the past 10 years. Moreover, cancer therapy administrated to "new" populations, especially elderly patients or patients with cardiovascular disease and/or coronary artery disease history, has increased considerably. According to the American College of Cardiology and American Heart Association (ACC/AHA), patients receiving chemotherapy can be considered in the A group of heart failure. Many cardiovascular adverse effects appear with cancer therapy and suspend treatment purchase, or leading to an alteration of quality of life, and increasing mortality risks. The most clinically evident cardiotoxicity and best known is the anthracyclines adverse effect. Other cytotoxic are associated with a significant risk of cardiovascular complications include alkylating agents such as 5-fluorouracil and paclitaxel. Cardiovascular adverse effects are associated with the use of targeted therapies such as tyrosine kinase inhibitors: trastuzumab, bevacizumab. At the same time, drugs used to hematological malignancies, as acid all-trans-retinoic acid and arsenic trioxide are cardiotoxics. The most serious cardiac complications of cancer therapies is heart congestive failure, mainly due to the use of anthracyclines, cyclophosphamide and trastuzumab, usually at high doses. Myocardial ischemia is mainly caused by interferon and antimetabolites. Other side effects may occur such as hypotension, hypertension, arrhythmias and conduction disturbances, pericarditis, and thromboembolic complications.

Published
2013

9. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant

Author

Leung, Nelson, Bridoux, Franck, Hutchison, Colin A, Nasr, Samih H, Cockwell, Paul, Fermand, Jean-Paul, Dispenzieri, Angela, Song, Kevin W, Kyle, Robert A, Renseigné, Non, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Pathology, medicine.medical_specialty, Immunology, Paraproteinemias, 030232 urology & nephrology, Renal function, MESH: Antineoplastic Agents, Alkylating, Monoclonal Gammopathy of Undetermined Significance, Biochemistry, MESH: Kidney Transplantation, 03 medical and health sciences, 0302 clinical medicine, MESH: Paraproteinemias, medicine, Humans, Antineoplastic Agents, Alkylating, Multiple myeloma, Kidney transplantation, Kidney, MESH: Kidney Diseases, MESH: Humans, business.industry, Cell Biology, Hematology, medicine.disease, Kidney Transplantation, 3. Good health, medicine.anatomical_structure, MESH: Kidney Failure, Chronic, 030220 oncology & carcinogenesis, MESH: Monoclonal Gammopathy of Undetermined Significance, Monoclonal, Disease Progression, Kidney Failure, Chronic, [SDV.IMM]Life Sciences [q-bio]/Immunology, Kidney Diseases, MESH: Disease Progression, Clone (B-cell biology), business, Monoclonal gammopathy of undetermined significance, Monoclonal Immunoglobulin Deposition Disease
Abstract

Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.

Published
2012

10. Waiting times before initiation of radiotherapy might not affect outcomes for patients with glioblastoma: a French retrospective analysis of patients treated in the era of concomitant temozolomide and radiotherapy

Author

Renaud de Crevoisier, Maud Aumont, Pierre Verrelle, Aymeri Huchet, Marie Pierre Sunyach, Christine Kerr, Sandrine Vinchon-Petit, Pierre Yves Bondiau, Jean Philippe Maire, Chantal Henzen, Fernand Missohou, Valérie Bernier, Xavier Durando, Georges Noël, Jean-Baptiste Clavier, Luc Taillandier, Philippe Collin, Emilie Le Rhun, A. d’Hombres, Jean Leon Lagrange, Loïc Feuvret, F. Thillays, Gilles Truc, D. Atlani, Centre Paul Strauss, CRLCC Paul Strauss, CHU Bordeaux [Bordeaux], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre René Gauducheau, CRLCC René Gauducheau, Centre Léon Bérard [Lyon], CRLCC Eugène Marquis (CRLCC), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre Alexis Vautrin (CAV), Centre Paul Papin, CRLCC Paul Papin, CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Neuro-Oncologie [CHRU Nancy], and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)

Subjects
Male, Cancer Research, Multivariate analysis, Neurology, Time Factors, Survival, medicine.medical_treatment, MESH: Antineoplastic Agents, Alkylating, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Radiotherapy Dosage, MESH: Chemoradiotherapy, Aged, 80 and over, MESH: Aged, Univariate analysis, MESH: Middle Aged, Brain Neoplasms, MESH: Glioblastoma, Radiotherapy Dosage, Chemoradiotherapy, MESH: Follow-Up Studies, Middle Aged, Prognosis, 3. Good health, Dacarbazine, Survival Rate, Oncology, MESH: Waiting Lists, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, medicine.drug, Waiting time, Adult, medicine.medical_specialty, Waiting Lists, MESH: Survival Rate, Affect (psychology), Glioblastoma multiforme, MESH: Dacarbazine, MESH: Prognosis, 03 medical and health sciences, medicine, Temozolomide, Humans, Antineoplastic Agents, Alkylating, Aged, Retrospective Studies, MESH: Humans, Radiotherapy, business.industry, MESH: Time Factors, MESH: Adult, MESH: Retrospective Studies, MESH: Male, Surgery, Radiation therapy, MESH: France, Concomitant, Neurology (clinical), business, Glioblastoma, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

International audience; Purpose of this study was to determine the effect of waiting time for radiotherapy on overall survival of patients with glioblastoma treated in the EORTC-NCIC trial at 18 centers in France. A total of 400 adult patients with glioblastoma who were treated between January 1, 2006 and December 31, 2006 were included. There were 282 patients with "minimum criteria" according to the EORTC-NCIC trial: (i) concurrent chemotherapy with temozolomide; and (ii) age between 18 and 70 years old. Among these patients, 229 were treated with adjuvant temozolomide and were classified as "maximal criteria". One-hundred and eighteen patients were in the "without minimal criteria" group. Waiting time from the first symptom (FS-RT), pathology diagnosis (P-RT), multidisciplinary meeting (MM-RT), surgery (S-RT), and CT scan for delineation (CT-RT) until the start of radiotherapy were recorded. Median follow-up for all patients was 327 days. Overall, median FS-RT, P-RT, MM-RT, CT-RT, and S-RT times were 77, 36, 32, 12, and 41 days, respectively. Median, and 12 and 24-month overall survival were 409 days, and 56.3 ± 2.1 % and 27.6 ± 2.6 %, respectively. Univariate analysis failed to reveal a difference in survival, irrespective of the delay. In multivariate analysis, independent favorable prognostic factors for overall survival were age (p ≤ 0.0001) and type of surgery (p = 0.0006). In this large series treated during the EORTC-NCIC protocol period, waiting time until radiotherapy did not seem to affect patient outcome.

Published
2012

11. Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma

Author

Jacqueline Lehmann-Che, Pascal Chastagner, Hana Janouskova, Catherine Bossert, Sophie Martin, Jan Teisinger, Dominique Guenot, Eric Guérin, Anne Maglott, David Y. Leger, Sophie Pinel, Fanny Noulet, François Plénat, Julien Godet, Monique Dontenwill, Natacha Entz-Werle, Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Signalisation, Génomique et Recherche Translationnelle en Oncologie (SIGRETO), Université Henri Poincaré - Nancy 1 (UHP), Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, medicine.medical_treatment, MESH: Piperazines, MESH: Antineoplastic Agents, Alkylating, Piperazines, law.invention, Mice, 0302 clinical medicine, law, Gene expression, Cytotoxic T cell, MESH: Animals, MESH: Tumor Suppressor Protein p53, MESH: Treatment Outcome, 0303 health sciences, Brain Neoplasms, MESH: Glioblastoma, Imidazoles, MESH: Drug Resistance, Neoplasm, 3. Good health, Dacarbazine, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, MESH: Imidazoles, medicine.drug, Integrin alpha5beta1, MESH: Cell Line, Tumor, Integrin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Dacarbazine, 03 medical and health sciences, Glioma, Cell Line, Tumor, medicine, Temozolomide, Animals, Humans, Antineoplastic Agents, Alkylating, MESH: Mice, 030304 developmental biology, Chemotherapy, MESH: Humans, MESH: Integrin alpha5beta1, Activator (genetics), medicine.disease, Drug Resistance, Neoplasm, biology.protein, Cancer research, Suppressor, Tumor Suppressor Protein p53, Glioblastoma
Abstract

Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of α5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the α5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, α5β1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high α5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between α5β1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that α5β1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of α5β1 integrin. Cancer Res; 72(14); 3463–70. ©2012 AACR.

Published
2012

12. High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome

Author

Jean-Claude Brouet, Bruno Royer, Arnaud Jaccard, Dominique Bordessoule, Jean-Paul Fermand, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), and Carrion, Claire

Subjects
Male, MESH: Remission Induction, MESH: Combined Modality Therapy, Pathology, MESH: Immunoglobulins, medicine.medical_treatment, MESH: POEMS Syndrome, Hematopoietic stem cell transplantation, MESH: Antineoplastic Agents, Alkylating, Plasma cell, Biochemistry, MESH: Dose-Response Relationship, Drug, Medicine, Melphalan, MESH: Treatment Outcome, MESH: Plasma Cells, MESH: Middle Aged, Remission Induction, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Combined Modality Therapy, MESH: Transplantation, Autologous, Treatment Outcome, medicine.anatomical_structure, POEMS Syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Stem cell, Adult, medicine.medical_specialty, NLM, [SDV.IMM] Life Sciences [q-bio]/Immunology, Plasma Cells, Immunology, Plasma cell dyscrasia, Immunoglobulins, MESH: Nervous System Diseases, Transplantation, Autologous, MESH: Melphalan, Humans, Antineoplastic Agents, Alkylating, MESH: Hematopoietic Stem Cell Transplantation, POEMS syndrome, MESH: Humans, Dose-Response Relationship, Drug, business.industry, MESH: Clone Cells, MESH: Adult, Cell Biology, medicine.disease, MESH: Male, Clone Cells, Transplantation, Bone marrow, Nervous System Diseases, business, MESH: Female, Monoclonal gammopathy of undetermined significance
Abstract

We treated 5 patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and multifocal bone lesions or diffuse bone marrow plasmacytic infiltration with high-dose therapy (HDT) and autologous blood stem cell transplantation. In all cases, the treatment produced remission of plasma cell proliferation associated with marked improvement in the patients' performance status, neurologic symptoms, and other manifestations of the syndrome. HDT with stem cell support should be investigated further as a therapeutic option in patients with POEMS syndrome and disseminated plasma cell dyscrasia.

Published
2002

13. Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy

Author

André Nicolas, Otto Pritsch, Sophie Viel, Sebastian Amigorena, Pablo Oppezzo, Adele Heitzmann, Xavier Sastre-Garau, Pascale Hubert, Eduardo Osinaga, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Département de Biologie des Tumeurs, Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Departamento de inmunobiologia, Facultad de Medicina- Universidad de la República [Montevideo] (UCUR), This work was financially supported by the Institut National de la Sante et de la Recherche Medicale, the Association pour la Recherche sur le Cancer (ARC), the Institut Curie, the EC grant ENCITE, Health-F5-2008-201842, the Institut National du Cancer (INCa)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut Curie, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSTITUT CURIE, Réseau International des Instituts Pasteur ( RIIP ) -Institut Pasteur de Montevideo, and Universidad de la República-Facultad de Medicina

Subjects
Immunological Synapses, Antibodies, Neoplasm, medicine.medical_treatment, MESH : Breast Neoplasms, MESH: Neutrophils, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, MESH : Neutrophils, Mice, MESH : Antibody-Dependent Cell Cytotoxicity, 0302 clinical medicine, Antibody Specificity, MESH: Animals, MESH : Tumor Microenvironment, MESH : Receptors, IgG, MESH : Macrophages, Ovarian Neoplasms, 0303 health sciences, MESH: Antigens, Tumor-Associated, Carbohydrate, Antibodies, Monoclonal, MESH: Cystadenocarcinoma, Serous, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Monoclonal, MESH: Immunization, Passive, Antibody, MESH: Receptors, IgG, Monoclonal antibody, MESH : Antigens, Tumor-Associated, Carbohydrate, 03 medical and health sciences, Antigen, In vivo, Humans, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Humans, Macrophages, MESH : Humans, Antibody-Dependent Cell Cytotoxicity, Immunization, Passive, MESH: Cyclophosphamide, Immunotherapy, Cystadenocarcinoma, Serous, MESH: Antibodies, Monoclonal, Humanized, MESH: Female, Cancer Research, MESH: Combined Modality Therapy, MESH : Immunization, Passive, Neutrophils, MESH: Antineoplastic Agents, Alkylating, MESH: Tumor Microenvironment, Tumor Microenvironment, MESH : Female, MESH : Cyclophosphamide, MESH : Immunological Synapses, MESH : Antibody Specificity, MESH : Cystadenocarcinoma, Serous, Antibody-dependent cell-mediated cytotoxicity, Mice, Inbred BALB C, biology, Combined Modality Therapy, MESH: Ovarian Neoplasms, MESH : Antibodies, Monoclonal, Female, MESH : Antibodies, Neoplasm, MESH : Mammary Neoplasms, Experimental, MESH: Cell Line, Tumor, medicine.drug_class, MESH : Antineoplastic Agents, Alkylating, MESH: Mammary Neoplasms, Experimental, MESH: Mice, Inbred BALB C, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, MESH : Antibodies, Monoclonal, Humanized, Cell Line, Tumor, MESH: Immunological Synapses, MESH : Mice, medicine, MESH: Antibody-Dependent Cell Cytotoxicity, Animals, Antigens, Tumor-Associated, Carbohydrate, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Antibody Specificity, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Innate immune system, MESH : Ovarian Neoplasms, MESH : Cell Line, Tumor, Receptors, IgG, Mammary Neoplasms, Experimental, MESH: Macrophages, Trastuzumab, Molecular biology, MESH: Antibodies, Neoplasm, biology.protein, MESH : Animals, MESH : Combined Modality Therapy, MESH: Breast Neoplasms
Abstract

Antibody-dependent cell cytotoxicity (ADCC) plays a critical role in monoclonal antibody (mAb)-mediated cancer therapy. ADCC, however, has not been directly shown in vivo but inferred from the requirement for IgG Fc receptors (FcγR) in tumor rejection in mice. Here, we investigated the mechanism of action of a Tn antigen-specific chimeric mAb (Chi-Tn), which binds selectively to a wide variety of carcinomas, but not to normal tissues, in both humans and mice. Chi-Tn mAb showed no direct toxicity against carcinomas cell lines in vitro but induced the rejection of a murine breast tumor in 80% to 100% of immunocompetent mice, when associated with cyclophosphamide. Tumor rejection was abolished in Fc receptors–associated γ chain (FcR-γ)–deficient mice, suggesting a role for ADCC. Indeed, tumor cells formed stable conjugates in vivo with FcR-γ chain-expressing macrophages and neutrophils in Chi-Tn mAb-treated but not in control mAb-treated mice. The contact zone between tumor cells and ADCC effectors accumulated actin, FcγR and phospho-tyrosines. The in vivo formed ADCC synapses were organized in multifocal supra-molecular activation clusters. These results show that in vivo ADCC mediated by macrophages and neutrophils during tumor rejection by Chi-Tn mAb involves a novel type of multifocal immune synapse between effectors of innate immunity and tumor cells. Cancer Res; 71(15); 5134–43. ©2011 AACR.

Published
2011

14. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice

Author

Daniel Scherman, Guy G. Chabot, Johanne Seguin, Yasmine S. Touil, Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chabot, Guy, Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Tumor Burden, Flavonols, MESH : Antineoplastic Combined Chemotherapy Protocols, MESH: Cell Cycle, Pharmacology, Toxicology, MESH : Flavonoids, Mice, 0302 clinical medicine, Cell Movement, Antineoplastic Combined Chemotherapy Protocols, MESH : Cell Proliferation, MESH : Cell Movement, Pharmacology (medical), MESH: Animals, MESH: Endothelial Cells, MESH: Cell Movement, ComputingMilieux_MISCELLANEOUS, MESH : Cell Survival, 0303 health sciences, MESH : Tumor Burden, Neovascularization, Pathologic, Cell Cycle, Tubulin Modulators, endothelial cells, Tumor Burden, 3. Good health, Endothelial stem cell, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, MESH: Cell Survival, 030220 oncology & carcinogenesis, Growth inhibition, fisetin, MESH: Antineoplastic Agents, Phytogenic, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, MESH : Carcinoma, Lewis Lung, MESH : Cell Cycle, MESH : Angiogenesis Inhibitors, Humans, Antineoplastic Agents, Alkylating, EA⋅hy 926, MESH: Humans, MESH : Endothelial Cells, MESH : Humans, MESH : Neovascularization, Pathologic, MESH: Cyclophosphamide, MESH: Cell Line, Mice, Inbred C57BL, chemistry, Lewis lung carcinoma, cyclophosphamide, MESH: Female, MESH: Flavonoids, MESH: NIH 3T3 Cells, MESH : Cell Line, Cancer Research, Angiogenesis, MESH : NIH 3T3 Cells, Angiogenesis Inhibitors, MESH: Antineoplastic Agents, Alkylating, MESH : Antineoplastic Agents, Phytogenic, Carcinoma, Lewis Lung, chemistry.chemical_compound, angiogenesis, MESH : Female, Cytotoxicity, MESH : Cyclophosphamide, MESH: Angiogenesis Inhibitors, MESH: Carcinoma, Lewis Lung, cytotoxicity, Female, EA*hy 926 endothelial cells, Cell Survival, MESH : Antineoplastic Agents, Alkylating, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Mice, Inbred C57BL, Biology, Cell Line, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, MESH : Mice, MESH: Tubulin Modulators, Animals, flavonoid, MESH: Mice, Cell Proliferation, 030304 developmental biology, Flavonoids, Cell growth, MESH : Tubulin Modulators, Antineoplastic Agents, Phytogenic, NIH 3T3 Cells, MESH : Animals, antitumour activity, MESH: Neovascularization, Pathologic, Fisetin
Abstract

International audience; PURPOSE: The natural flavonoid fisetin was recently identified as a lead compound that stabilizes endothelial cell microtubules. In this study, we investigated the antiproliferative and antiangiogenic properties of fisetin in vitro and in vivo. METHODS: Fisetin cytotoxicity was evaluated using Lewis lung carcinoma cells (LLC), endothelial cells and NIH 3T3 cells. Endothelial cell (EC) migration and capillary-like structure formation were evaluated using EAhy 926 cells. In vivo tumour growth inhibition studies were performed using LLC-bearing mice treated with fisetin and/or cyclophosphamide (CPA). RESULTS: The fisetin IC(50) was 59 μM for LLC and 77 μM for EC cells, compared to 210 μM for normal NIH 3T3 cells (24 h). Fisetin inhibited EC migration and capillary-like structure formation at non-cytotoxic concentrations (22-44 μM). In mice, fisetin inhibited angiogenesis assessed using the Matrigel plug assay. In LLC-bearing mice, fisetin produced a 67% tumour growth inhibition (223 mg/kg, intraperitoneal), similar to the 66% produced by low-dose CPA (30 mg/kg, subcutaneous). When fisetin and CPA were combined, however, a marked improvement in antitumour activity was observed (92% tumour growth inhibition), with low systemic toxicity. Tumour histology showed decreased microvessel density with either fisetin or CPA alone, and a dramatic decrease after the fisetin/CPA combination. CONCLUSIONS: We have shown that fisetin not only displays in vitro and in vivo antiangiogenic properties, but also can markedly improve the in vivo antitumour effect of CPA. We propose that this drug combination associating a non-toxic dietary flavonoid with a cytotoxic agent could advantageously be used in the treatment of solid tumours.

Published
2011

15. ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma

Author

Juan Carlos Tercero, Roberta Sanfilippo, Isabelle Ray-Coquard, Antoine Italiano, Audrey Laroche, Jean-Yves Blay, Armelle Laurand, Axel Le Cesne, Binh Bui, Jean Michel Coindre, Paolo G. Casali, Jacques Robert, Ian Judson, Antonio Nieto, Philippe Pourquier, José Enrique Garzón Jimeno, Laboratory of Solid Tumors Genetics, Nice University Hospital, Virologie Structurale, Institut Pasteur [Paris], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Equipe 11, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Service d'Oncologie Médicale, Centre Léon Bérard [Lyon], Département d'oncologie médicale, Institut Bergonié - CRLCC Bordeaux, Service de Pathologie, Institut Bergonié, Children’s Hospital La Fe, Laboratoire Aimé Cotton (LAC), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Scanella, Marie-Pierre, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut Pasteur [Paris] (IP), Service d'Oncologie Médicale, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatric Allergy and Pneumology Unit, Children's Hospital La Fe, HEC Montréal (HEC Montréal), Validation et identification de nouvelles cibles en oncologie (VINCO), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Service d'Oncologie Médicale

Subjects
Male, Cancer Research, DNA Repair, [SDV]Life Sciences [q-bio], Genes, BRCA1, MESH: Flow Cytometry, Apoptosis, MESH: Antineoplastic Agents, Alkylating, MESH: Base Sequence, MESH: Tetrahydroisoquinolines, 0302 clinical medicine, MESH: Endonucleases, Tetrahydroisoquinolines, MESH: Dioxoles, skin and connective tissue diseases, Trabectedin, Cell Line, Transformed, MESH: Aged, MESH: DNA Repair, Recombination, Genetic, 0303 health sciences, MESH: Middle Aged, Soft tissue sarcoma, MESH: Polymorphism, Single Nucleotide, Nuclear Proteins, Sarcoma, MESH: Transcription Factors, Middle Aged, Flow Cytometry, 3. Good health, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, MESH: Recombination, Genetic, Female, medicine.drug, MESH: DNA Primers, Adult, Xeroderma pigmentosum, Adolescent, DNA repair, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dioxoles, Polymorphism, Single Nucleotide, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, MESH: Cell Line, Transformed, RNA, Messenger, Antineoplastic Agents, Alkylating, 030304 developmental biology, MESH: RNA, Messenger, Aged, DNA Primers, MESH: Adolescent, MESH: Humans, Base Sequence, business.industry, MESH: Apoptosis, MESH: Adult, medicine.disease, Endonucleases, MESH: Male, MESH: Sarcoma, Cancer research, ERCC1, business, MESH: Female, MESH: Genes, BRCA1, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, Nucleotide excision repair, Transcription Factors
Abstract

BACKGROUND: The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS). METHODS: The authors analyzed excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross-complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate-use program. The 6-month progression-free rate (PFR), progression-free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log-rank tests. RESULTS: High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine-to-cytosine (T -> C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple-adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS. CONCLUSIONS: In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS. Cancer 2011;117:3445-56. (C) 2011 American Cancer Society.

Published
2011

16. Intérêt de la MGMT dans les gliomes. [MGMT analysis in gliomas]

Author

Quillien, Véronique, Vauléon, Elodie, Saikali, Stephan, Lesimple, Thierry, Hamlat, Abderrahmane, Etcheverry, Amandine, Mosser, Jean, Service de Biologie, CRLCC Eugène Marquis (CRLCC), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Département d'oncologie médicale [Rennes], Plate-forme transcriptome, Biogenouest®-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique Moléculaire et Génomique, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Biogenouest®, Service de Génétique moléculaire et Génomique [CHU Rennes], and De Villemeur, Hervé

Subjects
MESH: DNA Repair, MESH: Neoplasm Proteins, MESH: Humans, MESH: O(6)-Methylguanine-DNA Methyltransferase, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Antineoplastic Agents, Alkylating, MESH: Dacarbazine, digestive system diseases, MESH: Prognosis, gliomas, predictive factor, MESH: Glioma, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Brain Neoplasms, MGMT, prognostic factor, neoplasms
Abstract

International audience; MGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose.

Published
2011

17. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience

Author

Olivier Chabre, Richard Assaker, Françoise Borson-Chazot, Patrick François, Florence de Fraipont, Dominique Figarella-Branger, Jean-Guy Passagia, Stephan Gaillard, Sylvie Salenave, Nathalie Sturm, Philippe Caron, Philippe Chanson, Emmanuel Jouanneau, Christine Cortet-Rudelli, Michèle Bernier, Henry Dufour, Gérald Raverot, Aurélie Cornelius, Jacqueline Trouillas, Thierry Brue, M. Muller, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-UM Biochimie des Cancers et Biothérapies, CHU Grenoble-Institut de Biologie et Pathologie-Institut de Biologie et Pathologie, Laboratoire d'Imagerie Paramétrique (LIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Centre National de la Recherche Scientifique (CNRS), Centre de recherches métalexicographiques et dictionnairiques francophones (CRMDF), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Département d'endocrino-diabétologie, maladies de la nutrition, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Littoral, Environnement, Télédétection, Géomatique (LETG - Nantes), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN), Galaxies, Etoiles, Physique, Instrumentation (GEPI), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie et neuropathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service de neurochirurgie, Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Male, MESH: Carcinoma, Pituitary gland, MESH: Sequence Analysis, DNA, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, MESH: Antineoplastic Agents, Alkylating, Biochemistry, 0302 clinical medicine, Endocrinology, MESH: DNA Methylation, MESH: Middle Aged, MESH: Prolactinoma, Middle Aged, 3. Good health, Dacarbazine, ACTH-Secreting Pituitary Adenoma, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, France, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adult, endocrine system, medicine.medical_specialty, Adenoma, 030209 endocrinology & metabolism, Context (language use), MESH: Dacarbazine, O(6)-Methylguanine-DNA Methyltransferase, 03 medical and health sciences, Internal medicine, Temozolomide, medicine, Carcinoma, Humans, Neoplasm Invasiveness, Pituitary Neoplasms, Prolactinoma, MESH: Pituitary Neoplasms, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Antineoplastic Agents, Alkylating, neoplasms, Retrospective Studies, MESH: Humans, MESH: O(6)-Methylguanine-DNA Methyltransferase, business.industry, Biochemistry (medical), Pituitary tumors, O-6-methylguanine-DNA methyltransferase, MESH: Adult, MESH: Retrospective Studies, Sequence Analysis, DNA, MESH: Neoplasm Invasiveness, DNA Methylation, medicine.disease, MESH: Male, MESH: ACTH-Secreting Pituitary Adenoma, MESH: France, Pituitary carcinoma, business, MESH: Female
Abstract

International audience; CONTEXT: To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. OBJECTIVES: The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. PATIENTS: Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. DESIGN: MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. RESULTS: Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. CONCLUSION: Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status.

Published
2010

18. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study

Author

Jose I. Martinez, Maria G. Pallotta, Maciej Krzakowski, Nikolaos Throuvalas, Walter J. Curran, Christos Chouaid, Daniel Chua, Maya Gottfried, Institut de Recherche Pierre Fabre, Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE-PIERRE FABRE, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chua D ​​, M Krzakowski, C Chouaid, Pallotta MG, Martinez JI, M Gottfried, W Curran, and N Throuvalas .

Subjects
Oncology, Male, Cancer Research, MESH: Combined Modality Therapy, Lung Neoplasms, medicine.medical_treatment, Phases of clinical research, Kaplan-Meier Estimate, MESH: Antineoplastic Agents, Alkylating, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, MESH: Treatment Outcome, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Brain Neoplasms, Middle Aged, Combined Modality Therapy, 3. Good health, Dacarbazine, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Female, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, MESH: Dacarbazine, 03 medical and health sciences, Internal medicine, medicine, Temozolomide, Humans, Lung cancer, Antineoplastic Agents, Alkylating, MESH: Kaplan-Meier Estimate, 030304 developmental biology, Aged, Chemotherapy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, Surgery, MESH: Lung Neoplasms, Radiation therapy, MESH: Cranial Irradiation, Regimen, Concomitant, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cranial Irradiation, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung, Brain metastasis
Abstract

International audience; BACKGROUND: A previously published study of temozolomide concurrent with whole-brain radiation therapy (WBRT) reported significant improvement in response rates and a nonsignificant trend toward improved overall survival compared with WBRT alone in patients with brain metastases primarily from lung cancer. This study sought to confirm the benefit of adding temozolomide to WBRT in patients with non-small-cell lung cancer (NSCLC) with brain metastases. PATIENTS AND METHODS: This planned phase III study (target = 380 events) was converted to a phase II study (target = 70 events) because of poor enrollment. Patients with NSCLC and > or = 1 newly diagnosed brain lesion were randomized to WBRT (30 Gy in 10 fractions) alone or combined with temozolomide (75 mg/m2/day) for 21 or 28 days. Endpoints included overall survival and time to central nervous system (CNS) progression. RESULTS: Median overall survival and median time to CNS progression was 4.4 and 3.1 months in the WBRT + temozolomide arm (n = 47) versus 5.7 and 3.8 months in the WBRT arm (n = 48). However, there were imbalances in the percentages of patients receiving previous chemotherapy and with synchronous brain metastases. Adding temozolomide to WBRT increased the frequency of nausea, vomiting, alopecia, fatigue, anorexia, and constipation. Most adverse events were mild to moderate. CONCLUSION: The benefit of adding temozolomide to WBRT was not confirmed; however, the accrual goal for the planned phase III trial was not reached, and the study regimen differed from regimens used previously. Therefore, the role of temozolomide in treating brain metastases remains unresolved.

Published
2010

19. An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients

Author

François M. Vallette, Olivier Chinot, Carole Colin, Yannick Marie, Ahmed Idbaih, Michel Wager, Aurélien de Reyniès, François Ducray, Dominique Figarella-Branger, Marc Sanson, Emilie Thomas, Jérôme Honnorat, Jean-Yves Delattre, Lucie Karayan-Tapon, David S. Rickman, François Berger, Hervé Chneiweiss, Neuro-oncologie et neuro-inflammation, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association des Neuro-Oncologues d'Expression Française (ANOCEF), Hôpital de la Timone [CHU - APHM] (TIMONE)-CHU Marseille, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Cellules souches leucémiques et thérapeuthiques, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work is part of the national program Cartes d'Identité des Tumeurs (CIT) funded and developed by the Ligue Nationale Contre le Cancer., Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Psychiatrie et Neurosciences (U894), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Association des Neuro-Oncologues d'Expression Française ( ANOCEF ), Hôpital de la Timone [CHU - APHM] ( TIMONE ) -CHU Marseille, Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and BMC, Ed.

Subjects
Cancer Research, Microarray, MESH : Retrospective Studies, medicine.medical_treatment, MESH : Immunohistochemistry, MESH : Promoter Regions, Genetic, MESH: Antineoplastic Agents, Alkylating, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Transcriptome, 0302 clinical medicine, MESH: DNA Methylation, Gene expression, Promoter Regions, Genetic, Oligonucleotide Array Sequence Analysis, 0303 health sciences, CD68, MESH: Glioblastoma, MESH : Cyclin-Dependent Kinase Inhibitor p16, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, Oncology, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, MESH: Cyclin-Dependent Kinase Inhibitor p16, DNA methylation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, MESH : Antineoplastic Agents, Alkylating, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, In Vitro Techniques, lcsh:RC254-282, MESH : Glioblastoma, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Promoter Regions, Genetic, medicine, Humans, Antineoplastic Agents, Alkylating, Cyclin-Dependent Kinase Inhibitor p16, 030304 developmental biology, Retrospective Studies, Chemotherapy, MESH: Humans, Research, MESH : Humans, MESH: Immunohistochemistry, MESH: Retrospective Studies, DNA Methylation, Radiation therapy, MESH: Oligonucleotide Array Sequence Analysis, Cancer research, Glioblastoma, MESH : DNA Methylation
Abstract

Background The molecular characteristics associated with the response to treatment in glioblastomas (GBMs) remain largely unknown. We performed a retrospective study to assess the genomic characteristics associated with the response of GBMs to either first-line chemotherapy or radiation therapy. The gene expression (n = 56) and genomic profiles (n = 67) of responders and non-responders to first-line chemotherapy or radiation therapy alone were compared on Affymetrix Plus 2 gene expression arrays and BAC CGH arrays. Results According to Verhaak et al.'s classification system, mesenchymal GBMs were more likely to respond to radiotherapy than to first-line chemotherapy, whereas classical GBMs were more likely to respond to first-line chemotherapy than to radiotherapy. In patients treated with radiation therapy alone, the response was associated with differential expression of microenvironment-associated genes; the expression of hypoxia-related genes was associated with short-term progression-free survival (< 5 months), whereas the expression of immune genes was associated with prolonged progression-free survival (> 10 months). Consistently, infiltration of the tumor by both CD3 and CD68 cells was significantly more frequent in responders to radiotherapy than in non-responders. In patients treated with first-line chemotherapy, the expression of stem-cell genes was associated with resistance to chemotherapy, and there was a significant association between response to treatment and p16 locus deletions. Consistently, in an independent data set of patients treated with either radiotherapy alone or with both radiotherapy and adjuvant chemotherapy, we found that patients with the p16 deletion benefited from adjuvant chemotherapy regardless of their MGMT promoter methylation status, whereas in patients without the p16 deletion, this benefit was only observed in patients with a methylated MGMT promoter. Conclusion Differential expression of microenvironment genes and p16 locus deletion are associated with responses to radiation therapy and to first-line chemotherapy, respectively, in GBM. Recently identified transcriptomic subgroups of GBMs seem to respond differently to radiotherapy and to first-line chemotherapy.

Published
2010

20. Influence of the stereoisomeric position of the reactive acetate groups of the benzo[b]acronycine derivative S23906-1 on its DNA alkylation, helix-opening, cytotoxic, and antitumor activities

Author

Alain Pierré, Thomas Gaslonde, Christian Bailly, François Tillequin, Stéphane Léonce, Angèle Chiaroni, William Laine, Bruno Pfeiffer, Sabine Depauw, Sylvie Michel, Laurence Kraus-Berthier, Marie-Hélène David-Cordonnier, Gaëlle Lenglet, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
MESH: Catalytic Domain, MESH: Antineoplastic Agents, Alkylating, MESH: Acronine, chemistry.chemical_compound, DNA Adducts, Mice, 0302 clinical medicine, Catalytic Domain, MESH: Animals, 0303 health sciences, Chemistry, Cytotoxins, Stereoisomerism, Intercalating Agents, DNA Alkylation, MESH: Neoplasms, Experimental, Covalent bond, Mice, Inbred DBA, 030220 oncology & carcinogenesis, Molecular Medicine, MESH: Cell Division, medicine.symptom, MESH: Cytotoxins, MESH: DNA Adducts, Cell Division, MESH: Cell Line, Tumor, Stereochemistry, Acronine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, Cell Line, Tumor, medicine, Animals, Humans, Mode of action, MESH: Mice, Antineoplastic Agents, Alkylating, 030304 developmental biology, Cell Proliferation, Pharmacology, MESH: Humans, MESH: Mice, Inbred DBA, Neoplasms, Experimental, MESH: Stereoisomerism, MESH: Intercalating Agents, Mice, Inbred C57BL, Mechanism of action, Helix, Enantiomer, DNA
Abstract

International audience; S23906-1 is a benzo[b]acronycine derivative acting as a DNA-alkylating agent through covalent bonding to the exocyclic amino group of guanines and subsequent local opening of the DNA helix. This compound was selected for phase I clinical trials based on its efficient antitumor activity in experimental models and its unique mode of action. S23906-1 is the racemate of cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. Here, we evaluated the cytotoxic and antitumor activities of the two pure cis-enantiomers and investigated the mechanism of action of both cis- and trans-racemates and their enantiomers in terms of DNA alkylation potency and locally drug-induced DNA helix opening process. Reaction with glutathione, as a detoxification process, was also studied. The trans-compounds, both as racemate or separated enantiomers, were found less potent than the corresponding cis-derivatives. Among the cis-enantiomers, the most efficient one regarding DNA alkylation bears the acetate on the reactive C1 position in the R configuration, both on purified DNA and genomic DNA extracted from cell cultures. By contrast, the most cytotoxic and tumor-active enantiomer bears the C1-acetate in the S configuration. Distinct cellular DNA-alkylation levels or covalent bonding to glutathione could not explain the differences. However, we showed that the S and R orientations of the acetate on C1 asymmetric carbon lead to different local opening of the DNA, as visualized using nuclease S1 mapping. These different interactions could lead to modulated DNA-repair, protein/DNA interaction, and apoptosis processes.

Published
2009

21. Inter- and intrapatients comparison of WHO grade II glioma kinetics before and after surgical resection

Author

Luc Bauchet, Luc Taillandier, Philippe Peruzzi, Johan Pallud, Jacques Guyotat, Denys Fontaine, Marie-Hélène Baron, Emmanuel Mandonnet, Valérie Bernier, Laurent Capelle, Hugues Duffau, Réseau d'Etude des Gliomes, REG, Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurochirurgie, Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de neuro-radiologie, CHU Grenoble, Université de Reims Champagne-Ardenne (URCA), Service de neurochirurgie, Hospices Civils de Lyon (HCL), Centre Alexis Vautrin (CAV), Service de radiothérapie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Imagerie Fonctionnelle ( LIF ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], CHU Nice, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Reims Champagne-Ardenne ( URCA ), Hospices Civils de Lyon ( HCL ), Centre Alexis Vautrin ( CAV ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO)

Subjects
Male, MESH : Oligodendroglioma, MESH : Retrospective Studies, Databases, Factual, MESH: Antineoplastic Agents, Alkylating, Neurosurgical Procedures, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Linear Models, MESH: Magnetic Resonance Imaging, MESH: Glioma, 0302 clinical medicine, MESH : Child, MESH : Linear Models, MESH: Child, Medicine, Statistical analysis, MESH : Female, 10. No inequality, Child, MESH: Middle Aged, MESH : Neoplasm Recurrence, Local, MESH: Kinetics, Brain Neoplasms, General Medicine, MESH: Follow-Up Studies, Glioma, MESH : Adult, MESH : Neurosurgical Procedures, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Dacarbazine, MESH: Young Adult, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Disease Progression, MESH: Disease Progression, Female, Neurosurgery, MESH : Kinetics, MESH: Neoplasm Recurrence, Local, Surgical resection, Adult, medicine.medical_specialty, Adolescent, MESH : Male, MESH : Antineoplastic Agents, Alkylating, Oligodendroglioma, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Databases, Factual, Astrocytoma, MESH: Dacarbazine, 03 medical and health sciences, Young Adult, MESH : Adolescent, MESH : Magnetic Resonance Imaging, Linear regression, Grade II Glioma, Temozolomide, Humans, MESH : Middle Aged, MESH : Brain Neoplasms, MESH : Dacarbazine, MESH: Oligodendroglioma, Antineoplastic Agents, Alkylating, Retrospective Studies, Mean diameter, MESH: Adolescent, MESH: Humans, business.industry, WHO Grade II Glioma, MESH : Humans, MESH : Follow-Up Studies, MESH : Astrocytoma, MESH: Adult, MESH: Neurosurgical Procedures, MESH: Retrospective Studies, MESH : Disease Progression, MESH: Databases, Factual, MESH: Male, Surgery, Kinetics, MESH: Astrocytoma, MESH : Glioma, Linear Models, National database, Neurology (clinical), Neoplasm Recurrence, Local, Nuclear medicine, business, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

International audience; Grade II gliomas grow slowly and linearly (at rates about 4 mm/year) before undergoing anaplastic transformation. In order to analyze how surgery may affect radiological grade II glioma kinetics, we restrospectively reviewed our national database searching for patients operated on for a supratentorial grade II glioma between 1997 and 2007. We selected patients with at least two postoperative MRI with a minimal delay of 6 months. For each patient, postoperative residues were segmented on successive MRIs. Velocities of diameter expansion were estimated by linear regression of mean diameter evolution for each patient. Fifty-four patients fulfilled inclusion criteria. Median postoperative follow-up was 1.6 years with, on average, 3.4 MRI examinations per patient. Postoperative growth rates of mean diameter were normally distributed, around a mean value of 4.3 mm/year (SD = 3.2 mm/year). Statistical analysis showed no difference between this distribution and the distribution of preoperative growth rates in a previous series of 143 grade II gliomas. For a subset of 23 patients, delay between first MRI and surgery made it possible to estimate also preoperative growth rates. Intrapatient comparison revealed that growth rates were grossly unchanged for 80% of cases. In summary, inter- and intrapatient comparison of pre- and postoperative growth rates proves that surgery does not change grade II glioma dynamics, thus, acting as a cytoreduction.

Published
2009

22. Preparation, characterization and in vitro evaluation of a new nucleotide analogue prodrug cyclodextrin inclusion complexes

Author

Roudayna, Diab, Lars P, Jordheim, Ghania, Degobert, Suzanne, Peyrottes, Christian, Périgaud, Charles, Dumontet, Hatem, Fessi, Laboratoire d'automatique et de génie des procédés (LAGEP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)

Subjects
Cyclodextrins, Drug Carriers, Leukemia, MESH: Cell Line, Tumor, MESH: Materials Testing, Nucleotides, Drug Compounding, MESH: Diffusion, MESH: Antineoplastic Agents, Alkylating, MESH: Nucleotides, Diffusion, MESH: Cyclodextrins, Mice, MESH: Drug Carriers, Cell Line, Tumor, Materials Testing, MESH: Drug Compounding, MESH: Leukemia, Animals, Prodrugs, MESH: Animals, MESH: Prodrugs, Antineoplastic Agents, Alkylating, MESH: Mice, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug inclusion complexes, allowing it to be solubilized in water and hence to be used for in vitro and in vivo experiments. A molar ratio of the cyclodextrin: prodrug of 3 was sufficient to obtain complete solubilization of the prodrug. The inclusion complex was characterized by differential scanning calorimetry, which revealed the disappearance of the melting peak of the prodrug suggesting the formation of inclusion complex. Proton Nuclear Magnetic Resonance spectroscopy provided a definitive proof of the inclusion complex formation, which was evidenced by the large chemical shift displacements observed for protons located in the interior of the hydrophobic cyclodextrin cavity. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells. These results provided a basis for potential therapeutic applications of co-formulation of this new nucleotide analogue with hydroxypropyl-beta-CD in cancer therapy.

Published
2009

23. Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

Author

Siddiqui, B, Del Valle, L, Morellet, M, Cui, C, Ghafouri, M, Mukerjee, R, Urbanska, K, Fan, S, Pattillo, B, Deshmane, S, Kiani, K, Ansari, A, Khalili, K, Roques, B., Reiss, K, Bouaziz, B, Amini, A, Srinivasan, A, Sawaya, B, Siddiqui, K, Morellet, N., Cui, J., Mukerjee, M, Pattillo, C, Deshmane, L, Ansari, R., Roques, R, Bouaziz, S., Amini, S, Srinivasan, S., Sawaya, S, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Ecosystèmes forestiers (UR EFNO), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Space and Atmospheric Physics Group [London], Blackett Laboratory, Imperial College London-Imperial College London, Institut d'électronique fondamentale (IEF), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), inconnu, and Inconnu

Subjects
Cancer Research, Cell cycle checkpoint, Ku80, viruses, MESH: Amino Acid Sequence, MESH: Antineoplastic Agents, Alkylating, medicine.disease_cause, MESH: vpr Gene Products, Human Immunodeficiency Virus, MESH: HIV-1, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Animals, MESH: Anti-HIV Agents, 0303 health sciences, Ku70, Mice, Inbred C3H, virus diseases, vpr Gene Products, Human Immunodeficiency Virus, 3. Good health, Cell biology, Molecular mimicry, MESH: Mutagenesis, Site-Directed, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030220 oncology & carcinogenesis, MESH: Molecular Mimicry, Female, Programmed cell death, MESH: Cell Line, Tumor, DNA damage, Anti-HIV Agents, Molecular Sequence Data, Biology, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Animals, Humans, MESH: Tumor Suppressor Proteins, Amino Acid Sequence, MESH: Mice, Inbred C3H, Molecular Biology, Antineoplastic Agents, Alkylating, MESH: Mice, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, MESH: Molecular Sequence Data, Tumor Suppressor Proteins, Mutagenesis, Molecular Mimicry, biochemical phenomena, metabolism, and nutrition, Molecular biology, Protein Structure, Tertiary, MESH: Cisplatin, HIV-1, Mutagenesis, Site-Directed, Cisplatin, Carcinogenesis, MESH: Female, DNA Damage
Abstract

International audience; The human immunodeficiency virus type 1 (HIV-1) viral protein R (vpr) gene is an evolutionarily conserved gene among the primate lentiviruses. Several functions are attributed to Vpr including the ability to cause cell death, cell cycle arrest, apoptosis and DNA damage. The Vpr domain responsible for DNA damage as well as the mechanism(s) through which Vpr induces this damage is unknown. Using site-directed mutagenesis, we identified the helical domain II within Vpr (aa 37-50) as the region responsible for causing DNA damage. Interestingly, Vpr Delta(37-50) failed to cause cell cycle arrest or apoptosis, to induce Ku70 or Ku80 and to suppress tumor growth, but maintained its capability to activate the HIV-1 LTR, to localize to the nucleus and to promote nonhomologous end-joining. In addition, our cytogenetic data indicated that helical domain II induced chromosomal aberrations, which mimicked those induced by cisplatin, an anticancer agent. This novel molecular mimicry function of Vpr might lead to its potential therapeutic use as a tumor suppressor.

Published
2008

24. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes

Author

Dominique Cathelin, L. Arnould, Sylvain Audia, Christophe Ferrand, Nicolas Larmonier, Bernard Bonnotte, Bruno Chauffert, Marc Maynadié, Alexandra Nicolas, Eric Solary, A L Fanton, P. Foucher, Andrew Bateman, B. Lorcerie, E. Bergoin, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Department of Paediatrics, Steele Children's Research Centre, University of Arizona, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Cancer Sciences Division, University of Southampton [Southampton], Saas, Philippe, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), University of Arizona, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, University of Southampton, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Male, MESH: Combined Modality Therapy, Translational Studies, medicine.medical_treatment, MESH : Aged, MESH: Antineoplastic Agents, Alkylating, T-Lymphocytes, Regulatory, Immune tolerance, MESH : T-Lymphocytes, Regulatory, 0302 clinical medicine, Immunophenotyping, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Antigens, CD45, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, IL-2 receptor, MESH : BCG Vaccine, Neoplasm Metastasis, MESH : Cyclophosphamide, MESH : Lymphocyte Count, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, MESH : Immune Tolerance, MESH : Reverse Transcriptase Polymerase Chain Reaction, FOXP3, Forkhead Transcription Factors, hemic and immune systems, Middle Aged, Combined Modality Therapy, 3. Good health, MESH : Forkhead Transcription Factors, MESH: BCG Vaccine, 030220 oncology & carcinogenesis, MESH : Immunophenotyping, MESH : Neoplasm Metastasis, BCG Vaccine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.drug, MESH: Lymphocyte Count, MESH: Immune Tolerance, Cyclophosphamide, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, MESH : Male, MESH : Antineoplastic Agents, Alkylating, Immunology, chemical and pharmacologic phenomena, MESH: Antigens, CD45, Metastatic carcinoma, 03 medical and health sciences, MESH: Forkhead Transcription Factors, medicine, Immune Tolerance, Humans, MESH : Middle Aged, Lymphocyte Count, Antineoplastic Agents, Alkylating, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH: T-Lymphocytes, Regulatory, MESH : Humans, MESH: Cyclophosphamide, Immunotherapy, T lymphocyte, MESH: Neoplasm Metastasis, MESH: Male, Leukocyte Common Antigens, business, MESH : Combined Modality Therapy, MESH: Female
Abstract

SummaryWe determined the number and functional status of CD4+CD25high regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9·2% of CD4+ T cells) compared to 24 healthy donors (7·1%). These cells expressed the transcription factor forkhead box P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) and intracellular CD152, and demonstrated a suppressive activity in vitro against CD4+CD25– autologous proliferation. At a single intravenous infusion, cyclophosphamide failed, in association with a non-specific immunotherapy by intratumoral bacille Calmette–Guérin (BCG), to modulate significantly Treg numbers or function. Metastatic cancer is associated with an expansion of peripheral blood CD4+CD25highFoxP3+GITR+CD152+Treg cells whose immunosuppressive properties do not differ from those of healthy subjects. Moreover, cyclophosphamide administration may not represent an optimal therapy to eliminate Treg, which further underlines the need to identify specific agents that would selectively deplete these cells.

Published
2007

25. [Randomised phase II study evaluating oral combination chemotherapy (CCNU, cyclophosphamide, etoposide) and intravenous chemotherapy as second-line treatment for relapsed small cell bronchial carcinoma (Trial GFPC0501)]

Author

Gervais, R., Le Guen, Y., Le Caer, H., Paillotin, D., Chouaid, C., Renseigné, Non, Annesi-Maesano, Isabella, IFP Energies nouvelles (IFPEN), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), R Gervais, Le Guen Y, H Caer Le, Paillotin D, Chouaid C, and GFPC

Subjects
MESH: Remission Induction, MESH: Survival Rate, MESH: Antineoplastic Agents, Phytogenic, Administration, Oral, MESH: Vincristine, MESH: Lomustine, MESH: Antineoplastic Agents, Alkylating, MESH: Health Resources, MESH: Doxorubicin, Lomustine, Antineoplastic Combined Chemotherapy Protocols, Humans, MESH: Antibiotics, Antineoplastic, Carcinoma, Small Cell, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Bronchial Neoplasms, MESH: Etoposide, MESH: Treatment Outcome, Aged, Etoposide, MESH: Aged, MESH: Humans, Antibiotics, Antineoplastic, Bronchial Neoplasms, Remission Induction, MESH: Quality of Life, MESH: Cyclophosphamide, MESH: Carcinoma, Small Cell, MESH: Injections, Intravenous, Antineoplastic Agents, Phytogenic, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Doxorubicin, Vincristine, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Administration, Oral, Injections, Intravenous, Quality of Life, Health Resources, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Recurrence, Local, MESH: Neoplasm Recurrence, Local
Abstract

International audience; BACKGROUND: There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors. METHODS: The aim of this phase II randomised trial (GFPC0501) is to compare, in patients with progressive SCLC after first-line platinum based chemotherapy, oral multi drug chemotherapy (CCNU, cyclophosphamide, etoposide) and classical intravenous chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in terms of tolerability, efficacy (response rate, median one year survival and overall survival), quality of life and consumption of health care resources. Based on a two-stage Bryant and Day approach, this study will require a total of 138 patients with an interim analysis of the first 38. EXPECTED RESULTS: This trial will provide information on several aspects of second-line chemotherapy for patients with SCLC. Thirty six patients have been enrolled in 16 centres by December 2006 and the results of the interim analysis will be available in June 2007.

Published
2007

26. [Treatment of AL amyloidosis, current data]

Author

A, Jaccard, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Amyloid, MESH: Remission Induction, Anti-Inflammatory Agents, MESH: Antineoplastic Agents, Alkylating, Dexamethasone, MESH: Melphalan, Humans, Multicenter Studies as Topic, MESH: Amyloidosis, Antineoplastic Agents, Alkylating, Melphalan, ComputingMilieux_MISCELLANEOUS, MESH: Hematopoietic Stem Cell Transplantation, Randomized Controlled Trials as Topic, MESH: Amyloid, MESH: Humans, Remission Induction, Hematopoietic Stem Cell Transplantation, Amyloidosis, MESH: Drug Therapy, Combination, MESH: Randomized Controlled Trials as Topic, MESH: Anti-Inflammatory Agents, MESH: Dexamethasone, MESH: Multicenter Studies as Topic, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination
Abstract

International audience

Published
2006

27. [Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhances late toxicities]

Author

Toledano, A., Garaud, P., Serin, D., Fourquet, A., Bosset, Jean-François, Miny-Buffet, J., Favre, A., Azria, David, Body, G., Le Floch, O., Calais, G., Department of Applied Mathematics and Statistics [Santa Cruz], University of California [Santa Cruz] ( UCSC ), Laboratoire du Service d'Oncologie Médicale, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), University of California [Santa Cruz] (UCSC), University of California-University of California, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)

Subjects
MESH : Single-Blind Method, MESH : Antineoplastic Combined Chemotherapy Protocols, MESH : Aged, MESH : Prospective Studies, Skin Pigmentation, MESH: Antineoplastic Agents, Alkylating, MESH : Breast Neoplasms, Mastectomy, Segmental, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Antineoplastic Combined Chemotherapy Protocols, MESH: Dose Fractionation, Single-Blind Method, MESH : Female, Breast, Prospective Studies, MESH : Atrophy, MESH: Breast, MESH : Cyclophosphamide, MESH: Telangiectasis, MESH: Aged, MESH: Middle Aged, MESH : Chemotherapy, Adjuvant, MESH: Follow-Up Studies, Middle Aged, MESH : Adult, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Antineoplastic Agents, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, MESH: Fibrosis, MESH : Fibrosis, Female, MESH: Skin Pigmentation, MESH: Mitoxantrone, Adult, MESH: Radiotherapy, Adjuvant, MESH : Antineoplastic Agents, Alkylating, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Atrophy, MESH : Lymph Node Excision, MESH : Radiotherapy, Adjuvant, Humans, MESH : Middle Aged, Telangiectasis, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Mastectomy, Segmental, MESH : Mastectomy, Segmental, Aged, MESH: Humans, MESH : Telangiectasis, MESH: Lymph Node Excision, MESH : Dose Fractionation, MESH : Humans, MESH: Cyclophosphamide, MESH: Adult, MESH : Follow-Up Studies, MESH: Single-Blind Method, Fibrosis, MESH: Prospective Studies, MESH : Mitoxantrone, Lymph Node Excision, MESH: Antineoplastic Agents, MESH : Breast, Radiotherapy, Adjuvant, Dose Fractionation, Radiation, Atrophy, Mitoxantrone, MESH : Skin Pigmentation, MESH: Female, MESH: Breast Neoplasms, Follow-Up Studies
Abstract

International audience; PURPOSE: In 1996, a multicenter randomized study comparing after breast-conservative surgery, sequential vs concurrent adjuvant chemotherapy (CT) with radiation therapy (RT) was initiated (ARCOSEIN study). Seven hundred sixteen patients were included in this trial. After a median follow-up of 6.7 (4.3-9) years, we decided to prospectively evaluate the late effects of these two strategies. PATIENTS AND METHODS: A total of 297 patients were asked to follow-up from the five larger including institutions. Seventy-two percent (214 patients) were eligible for late toxicity. After breast-conserving surgery with axillary dissection, patients were treated either with sequential treatment with CT first followed by RT (arm A) or CT administered concurrently with RT (arm B). In all patients, CT regimen combined mitoxantrone (12 mg/m(2)), 5-FU (500 mg/m(2)), and cyclophosphamide (500 mg/m(2)), 6 cycles (day 1-day 21). In arm B, patients received concurrently the first 3 cycles of CT with RT. In arm A, RT started 3 to 5 weeks after the 6th cycle of CT. Conventional RT was delivered to the whole breast using a 2 Gy-fraction protocol to a total dose of 50 Gy (+/-boost to the primary tumour bed). The assessment of toxicity was blinded to treatment and was graded by the radiation oncologist according to the LENT-SOMA scale. Skin pigmentation was also evaluated using a personal 5-points scoring system (excellent, good, moderate, poor, very poor). RESULTS: Among the 214 evaluated patients, 107 were treated in each arm. The two populations were homogeneous for patients', tumors' and treatment characteristics. Subcutaneous fibrosis (SF), telengectasia (T), skin pigmentation (SP), and breast atrophy (BA) were significantly increased in arm B. Twenty patients experienced grade superior or equal to 2 (SF) in arm B vs five in arm A (P=0.003). Twenty-five and seven patients showed grade superior or equal to 2 (T) in arm B and A, respectively (P=0.001). Forty-four and twenty patients showed grade superior or equal to 2 (BA) in arm B and A, respectively (P=0.0006). Thirty patients experienced grade superior or equal to 3 (SP) in arm B vs fifteen in arm A (P=0.02). No statistical difference was observed between the two arms concerning grade superior or equal to 2 pain, breast oedema, and lymphoedema. No deaths were caused by late toxicity. CONCLUSION: Following breast conserving surgery, the concurrent use of CT with RT is significantly associated with an increase incidence of grade 2 or greater late side effects.

Published
2006

28. Efficacy and toxicity of mitomycin, ifosfamide, and cisplatin (MIP) in patients with inoperable non-small cell lung cancer

Author

Thierry Urban, Michel Febvre, Arnaud Bedin, Christos Chouaid, Bernard Lebeau, M. Baud, Annesi-Maesano, Isabella, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Matériaux à Porosité Contrôlée (LMPC), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS), T urbain, Bedin A, M Baud, C Chouaid, M Febvre, B Lebeau, and Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ecole Nationale Supérieure de Chimie de Mulhouse-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Combined Modality Therapy, Cancer Research, Lung Neoplasms, medicine.medical_treatment, MESH: Antineoplastic Agents, Alkylating, Gastroenterology, MESH: Dose-Response Relationship, Drug, Mitomycins, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Medicine, Prospective Studies, Infusions, Intravenous, MESH: Treatment Outcome, MESH: Aged, education.field_of_study, MESH: Middle Aged, Ifosfamide, Antibiotics, Antineoplastic, MESH: Neoplasm Staging, Middle Aged, Combined Modality Therapy, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Oncology, Female, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, MESH: Radiotherapy, Adjuvant, MESH: Survival Rate, Population, Internal medicine, Humans, MESH: Ifosfamide, MESH: Antibiotics, Antineoplastic, MESH: Infusions, Intravenous, education, Lung cancer, Antineoplastic Agents, Alkylating, Aged, Neoplasm Staging, Cisplatin, Chemotherapy, MESH: Humans, Dose-Response Relationship, Drug, MESH: Mitomycins, business.industry, Mitomycin C, MESH: Adult, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Lung Neoplasms, Surgery, Regimen, MESH: Cisplatin, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Radiotherapy, Adjuvant, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung, Febrile neutropenia
Abstract

International audience; Seventy-two patients with advanced stage IIIB (42%) or stage IV (58%) non-small cell lung cancer (median age 57 years, Karnofsky PS 60-100) were treated with mitomycin C (6 mg/m2, day 1), ifosfamide (1500 mg/m2, days 1-3), and cisplatin (30 mg/m2, days 1-3) every 4 weeks. The objective response rate was 37% in the overall population; 50% in stage IIIB patients and 29% in stage IV patients. Twenty four patients achieved partial response (33%) and three patients achieved complete response. Despite this relatively high objective response rate, the overall median survival time was 32 weeks. The median survival was significantly better in stage IIIB patients (55 weeks) than in stage IV patients (25 weeks) (P = 0.003). MIP regimen was permanently suspended in 14 patients because of toxic events. Seventeen patients developed grade III or IV febrile neutropenia and two patients died from sepsis. Two patients experienced acute mitomycin peumonitis. Despite increased doses of cisplatin and ifosfamide, compared with the original description for MIC chemotherapy, with probably higher toxicity, no apparent increased response rate or median survival was observed in this study. The MIP regimen could be tested in a randomized trial in comparison with other administration plans in a comparable population.

Published
1996

29. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines

Author

Julien, Taieb, Nathalie, Chaput, Noël, Schartz, Stéphan, Roux, Sophie, Novault, Cédric, Ménard, François, Ghiringhelli, Magali, Terme, Antoine F, Carpentier, Guillaume, Darrasse-Jèze, Guillaume, Darrasse-Jèse, François, Lemonnier, Laurence, Zitvogel, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], This work is supported by a Poste d’accueil Institut National de la Santé et de la Recherche Médicale and Assistance Publique Hopitaux de Paris (to J.T.) and is supported by a European fellowship in the QLRT-2001-00093 and by Association de Recherche contre le Cancer (to N.C.). This work has also been supported by the EC ALLOSTEM grant, by DC THERA European grant, by the Association de Recherche contre le Cancer, and by the LIGUE LABELLISEE française contre le Cancer cancéropôle, Ile de France., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Novault, Sophie

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Melanoma, Experimental, MESH: Vaccines, Subunit, MESH: Adjuvants, Immunologic, CD8-Positive T-Lymphocytes, Pharmacology, MESH: Antineoplastic Agents, Alkylating, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH: Cancer Vaccines, Mice, 0302 clinical medicine, MESH: Cytoplasmic Vesicles, polycyclic compounds, Immunology and Allergy, MESH: Animals, IL-2 receptor, Cells, Cultured, Mice, Knockout, Mice, Inbred BALB C, MESH: Dendritic Cells, FOXP3, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], MESH: Melanoma, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Vaccines, Subunit, MESH: Immunotherapy, Adoptive, Female, hormones, hormone substitutes, and hormone antagonists, MESH: Cells, Cultured, MESH: Killer Cells, Natural, MESH: Mice, Transgenic, T cell, Immunology, MESH: Mice, Inbred BALB C, Mice, Transgenic, Biology, Major histocompatibility complex, Cancer Vaccines, Exosome, 03 medical and health sciences, Adjuvants, Immunologic, medicine, Animals, Humans, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Mice, MESH: Humans, MESH: T-Lymphocytes, Regulatory, Cytoplasmic Vesicles, MESH: Cyclophosphamide, Dendritic Cells, Immunotherapy, Microvesicles, CTL, biology.protein, MESH: Female, 030215 immunology
Abstract

Dendritic cell-derived exosomes (DEX) are nanomeric vesicles harboring MHC/peptide complexes capable of promoting primary T cell responses and tumor rejection in the presence of adjuvants. In this study, we show that, in the absence of adjuvants, DEX mediate potent Ag-dependent antitumor effects against preestablished tumors in mice pretreated with immunopotentiating dosing of cyclophosphamide. Cyclophosphamide could 1) abolish the suppressive function of CD4+CD25+Foxp3+ regulatory T cells, 2) markedly enhance the magnitude of secondary but not primary CTL responses induced by DEX vaccines, 3) synergize with DEX in therapy but not prophylaxis tumor models. Therefore, therapeutic vaccines such as DEX aimed at boosting tumor-primed effector T cells could benefit procedures that minimize the effects of CD4+CD25+ regulatory T cells.

Published
2006

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