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1. Acid-sensitive polyethylene glycol conjugates of doxorubicin: preparation, in vitro efficacy and intracellular distribution

Author

Luigi Messori, Peter Schumacher, Pierluigi Orioli, Felix Kratz, Clemens Unger, Heinz H. Fiebig, Thomas Roth, D. H. Paper, Paula C.A. Rodrigues, Rolf Mülhaupt, and Ulrich Beyer

Subjects
Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Polyethylene glycol, Biochemistry, Polyethylene Glycols, chemistry.chemical_compound, Drug Stability, Amide, Drug Discovery, PEG ratio, medicine, Tumor Cells, Cultured, Animals, Humans, Doxorubicin, Molecular Biology, Maleimide, Tumor Stem Cell Assay, Organic Chemistry, DNA, Hydrogen-Ion Concentration, chemistry, Doxorubicin Preparation, Microscopy, Fluorescence, Biophysics, Molecular Medicine, Cattle, Drug carrier, Ethylene glycol, medicine.drug
Abstract

Coupling anticancer drugs to synthetic polymers is a promising approach of enhancing the antitumor efficacy and reducing the side-effects of these agents. Doxorubicin maleimide derivatives containing an amide or acid-sensitive hydrazone linker were therefore coupled to alpha-methoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 20000 Da), alpha,omega-bis-thiopropionic acid amide poly(ethylene glycol) (MW 20000 Da) or alpha-tert-butoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 70000 Da) and the resulting polyethylene glycol (PEG) conjugates isolated through size-exclusion chromatography. The polymer drug derivatives were designed as to release doxorubicin inside the tumor cell by acid-cleavage of the hydrazone bond after uptake of the conjugate by endocytosis. The acid-sensitive PEG conjugates containing the carboxylic hydrazone bonds exhibited in vitro activity against human BXF T24 bladder carcinoma and LXFL 529L lung cancer cells with IC70 values in the range 0.02-1.5 microm (cell culture assay: propidium iodide fluorescence or colony forming assay). In contrast, PEG doxorubicin conjugates containing an amide bond between the drug and the polymer showed no in vitro activity. Fluorescence microscopy studies in LXFL 529 lung cancer cells revealed that free doxorubicin accumulates in the cell nucleus whereas doxorubicin of the acid-sensitive PEG doxorubicin conjugates is primarily localized in the cytoplasm. Nevertheless, the acid-sensitive PEG doxorubicin conjugates retain their ability to bind to calf thymus DNA as shown by fluorescence and visible spectroscopy studies. Results regarding the effect of an acid-sensitive PEG conjugate of molecular weight 20000 in the chorioallantoic membrane (CAM) assay indicate that this conjugate is significantly less embryotoxic than free doxorubicin although antiangiogenic effects were not observed.

Published
2000

2. Relationship between Physical Activity, Oxidative Stress, and Total Plasma Antioxidant Capacity in Spanish Children from the GENOBOX Study

Author

María D. Mesa, Rosaura Leis, Augusto Anguita-Ruiz, Azahara I. Rupérez, Concepción M. Aguilera, Luis A. Moreno, Angel Gil, Francisco Jesus Llorente-Cantarero, Francisco Javier Aguilar-Gómez, Gloria Bueno, Rocío Vázquez-Cobela, Mercedes Gil-Campos, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, [Llorente-Cantarero,FJ] Department of Specific Didactics, Faculty of Education, Maimónides Institute of Biomedicine Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain. [Llorente-Cantarero,FJ, Leis,R, Bueno,G, Anguita-Ruiz,A, Vázquez-Cobela,R, Moreno,LA, Gil,A, Aguilera,CM, Gil-Campos,M] CIBEROBN, (Physiopathology of Obesity and Nutrition) Institute of Health Carlos III (ISCIII), Madrid, Spain. [Aguilar-Gomez FJ, Gil-Campos,M] Metabolism and Investigation Unit, Reina Sofía University Hospital, Maimónides Institute of Biomedicine Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain. [Leis,R, Vázquez-Cobela,R] Unit of Investigation in Nutrition, Growth and Human Development of Galicia, Pediatric Department, University of Santiago de Compostela, Clinic University Hospital of Santiago, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. [Bueno,G] Pediatric Endocrinology Unit, Clinic University Hospital Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain. [Bueno,G, Rupérez,AI, Moreno,LA] GENUD Research Group, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria (IIS) Aragón, University of Zaragoza, Zaragoza, Spain. [Anguita-Ruiz,A, Mesa,MA, Aguilera,CM] Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology 'José Mataix', Center of Biomedical Research, University of Granada, Armilla, Granada, Spain. [Anguita-Ruiz,A, Aguilera,CM] Instituto de Investigación Biosanitaria ibs Granada, 18014 Granada, Spain., This research was funded by the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI11/02042, PI11/02059, PI11/01425, and PI16/00871, PI16/01301, PI16/01205) and RETIC (Redes temáticas de investigación cooperativa) (Red SAMID RD12/0026/0015). The authors also acknowledge Instituto de Salud Carlos III for personal funding of A.A.R: Contratos i-PFIS: doctorados IIS-empresa en ciencias y tecnologías de la salud de la convocatoria 2017 de la Acción Estratégica en Salud 2013–2016 (IFI17/00048). Á.G. was funded by the Research Plan of the Vice-Rectorate of Research and Transfer of the University of Granada, Spain This paper will be included in F.J.A. doctorate, under the 'Biomedicine Program' at the University of Córdoba, Spain.

Subjects
Antioxidant, Isoprostane, 8-hydroxy-2′-deoxyguanosine, Physiology, medicine.medical_treatment, Clinical Biochemistry, Physical fitness, physical activity, medicine.disease_cause, Biochemistry, Acelerometría, chemistry.chemical_compound, 0302 clinical medicine, Accelerometry, oxidative stress, 030212 general & internal medicine, Isoprostane F2α, Plasma total antioxidant capacity, Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress [Medical Subject Headings], Health Care::Health Care Economics and Organizations::Organizations::International Agencies::United Nations::World Health Organization [Medical Subject Headings], Total plasma, plasma total antioxidant capacity, Estrés oxidativo, Ejercicio físico, isoprostane F2, Antioxidant capacity, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Titrimetry::Colorimetry [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::Immunoassay::Immunoenzyme Techniques::Enzyme-Linked Immunosorbent Assay [Medical Subject Headings], 8-Hidroxi-2'-Desoxicoguanosina, medicine.medical_specialty, Physical activity, Article, 03 medical and health sciences, Internal medicine, isoprostane F2α, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Protective Agents::Antioxidants [Medical Subject Headings], medicine, accelerometry, Pysical activity, Molecular Biology, Redox homeostasis, business.industry, lcsh:RM1-950, 030229 sport sciences, Cell Biology, 8-hydroxy-20-deoxyguanosine, Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Physical Fitness [Medical Subject Headings], lcsh:Therapeutics. Pharmacology, chemistry, Oxidative stress, business
Abstract

The World Health Organization has recommended performing at least 60 min a day of moderate-to-vigorous physical activity (MVPA) and reducing sedentarism in children and adolescents to offer significant health benefits and mitigate health risks. Physical fitness and sports practice seem to improve oxidative stress (OS) status during childhood. However, to our knowledge, there are no data regarding the influence of objectively-measured physical activity (PA) and sedentarism on OS status in children and adolescents. The present study aimed to evaluate the influence of moderate and vigorous PA and sedentarism on OS and plasma total antioxidant capacity (TAC) in a selected Spanish population of 216 children and adolescents from the GENOBOX study. PA (light, moderate, and vigorous) and sedentarism (i.e., sedentary time (ST)) were measured by accelerometry. A Physical Activity-Sedentarism Score (PASS) was developed integrating moderate and vigorous PA and ST levels. Urinary 8-hydroxy-20-deoxyguanosine (8-OHdG) and isoprostane F2 (F2-IsoPs), as markers of OS, were determined by ELISA; and TAC was estimated by colorimetry using an antioxidant kit. A higher PASS was associated with lower plasma TAC and urinary 8-OHdG and F2-IsoPs, showing a better redox profile. Reduced OS markers (8-OHdG and F2-IsoPs) in children with higher PASS may diminish the need of maintaining high concentrations of antioxidants in plasma during rest to achieve redox homeostasis., Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI11/02042 PI11/02059 PI11/01425 PI16/00871 PI16/01301 PI16/01205, RETIC (Redes temáticas de investigación cooperativa) Red SAMID RD12/0026/0015, Instituto de Salud Carlos III European Commission IFI17/00048, Research Plan of the Vice-Rectorate of Research and Transfer of the University of Granada, Spain

Published
2021

3. Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation

Author

Antoine Chalopin, Benjamin Ory, Lidia Rodriguez Calleja, Marta Tellez Gabriel, Dominique Heymann, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], This paper was written as a part of research project which received funding from the Seventh Framework Program [(FP7/2007-2013) under grant agreement no. 264817—BONE-NET and this work was supported by the Fondation de France (Engt no. 16390)]., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Heymann, Dominique, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID

Subjects
0301 basic medicine, Epithelial-Mesenchymal Transition, Clinical Biochemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Biology, Cell enrichment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Circulating tumor cell, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Antigen, Single-cell analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Biomarkers, Tumor, Humans, Epithelial–mesenchymal transition, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Biochemistry (medical), Mesenchymal stem cell, Epithelial cell adhesion molecule, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Epithelial Cell Adhesion Molecule, Neoplastic Cells, Circulating, 3. Good health, 030104 developmental biology, chemistry, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Immunology, Cancer research, Personalized medicine, Single-Cell Analysis, business, Cell Adhesion Molecules
Abstract

BACKGROUND Circulating tumor cells (CTCs) are biomarkers for noninvasively measuring the evolution of tumor genotypes during treatment and disease progression. Recent technical progress has made it possible to detect and characterize CTCs at the single-cell level in blood. CONTENT Most current methods are based on epithelial cell adhesion molecule (EpCAM) detection, but numerous studies have demonstrated that EpCAM is not a universal marker for CTC detection because it fails to detect both carcinoma cells that undergo epithelial-mesenchymal transition (EMT) and CTCs of mesenchymal origin. Moreover, EpCAM expression has been found in patients with benign diseases. A large proportion of the current studies and reviews about CTCs describe EpCAM-based methods, but there is evidence that not all tumor cells can be detected using this marker. Here we describe the most recent EpCAM-independent methods for enriching, isolating, and characterizing CTCs on the basis of physical and biological characteristics and point out the main advantages and disadvantages of these methods. SUMMARY CTCs offer an opportunity to obtain key biological information required for the development of personalized medicine. However, there is no universal marker of these cells. To strengthen the clinical utility of CTCs, it is important to improve existing technologies and develop new, non–EpCAM-based systems to enrich and isolate CTCs.

Published
2016
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4. CCKA, but not CCKB, agonists suppress the hyperlocomotion induced by endogenous enkephalins, protected from enzymatic degradation by systemic RB 101

Author

Bernard P. Roques, Valérie Daugé, P. J. Corringer, Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We wish to thank Dr. A. Beaumont and Dr.J.Vierek for the stylistic revision of the paper, and C. Dupuis for her assistance in drafting it. We are grateful to S.Turcaud and P. Coric for the synthesis of RB 101., Cova Rodrigues, Ana, 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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-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
Male, Enkephalin, Narcotic Antagonists, [SDV]Life Sciences [q-bio], Clinical Biochemistry, RB-101, Devazepide, Inhibitor of enkephalin degradation, MESH: Amino Acid Sequence, Toxicology, Biochemistry, MESH: Benzodiazepinones, Behavioral Neuroscience, Mice, 0302 clinical medicine, Interactions between CCK and enkephalins, MESH: Enkephalins, MESH: Animals, Disulfides, Enzyme Inhibitors, MESH: Cholecystokinin, MESH: Peptide Fragments, MESH: Devazepide, 0303 health sciences, Benzodiazepinones, MESH: Receptors, Cholecystokinin, Chemistry, digestive, oral, and skin physiology, Enkephalins, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Naltrexone, CCKA and CCKB agonists, MESH: Motor Activity, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Enzyme Inhibitors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Naltrexone, MESH: Narcotic Antagonists, Cholecystokinin, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Agonist, Locomotor activity, medicine.medical_specialty, medicine.drug_class, Phenylalanine, Molecular Sequence Data, Motor Activity, 03 medical and health sciences, MESH: Phenylalanine, Naltrindole, Internal medicine, medicine, Animals, MESH: Disulfides, Amino Acid Sequence, Opioid peptide, MESH: Mice, Biological Psychiatry, 030304 developmental biology, Pharmacology, MESH: Molecular Sequence Data, Antagonist, Peptide Fragments, MESH: Male, Endocrinology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Receptors, Cholecystokinin, Physiological agonism and antagonism, 030217 neurology & neurosurgery
Abstract

International audience; Interactions between CCKergic and enkephalinergic systems were studied in mice using behavioral responses measured in Animex. The hyperlocomotion induced by 5 mg/kg of RB 101, a mixed inhibitor of enkephalin-degrading enzymes able to cross the blood-brain barrier, was previously shown to be mediated by delta-opioid receptor stimulation. The IP administration of a CCKA agonist, Boc-Tyr-Lys-(CONH-o-tolyl)-Asp-Phe-NH2 (0.1, 1, 10 micrograms/kg), suppressed the hyperlocomotion produced by IV injection of 5 mg/kg of RB 101. The effect of the CCKA agonist was suppressed by a selective CCKA antagonist, devazepide, injected IP at doses of 20 and 200 micrograms/kg and was potentiated by the selective delta-opioid antagonist naltrindole at the doses of 0.03 mg/kg. IP injection of the selective CCKB agonist BC 264 (0.1-1 mg/kg) did not modify the RB 101-induced hyperlocomotor effect. These results reinforce the observed physiological antagonism between the endogenous CCK and opioid systems but are at variance with the responses measured in stressful conditions. It is concluded that CCKA, but not CCKB, receptor activation counteracts the opioid-related hyperlocomotion.

Published
1995
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