19,429 results on '"Antimetabolites, Antineoplastic"'
Search Results
2. Natural Killer Cell (CYNK-001) Infusions in Adults With AML (CYNK001AML01)
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- 2023
3. Natural Killer Cell (CYNK-001) Infusions in Adults With COVID-19 (CYNKCOVID)
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Access to Advanced Health Institute (AAHI), Lung Biotechnology PBC, and California Institute for Regenerative Medicine (CIRM)
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- 2022
4. High-dose methotrexate pharmacokinetics and its impact on prognosis of paediatric acute lymphoblastic leukaemia patients: A population pharmacokinetic study.
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Chen X, Li J, Yu L, Hu W, Cai J, Wang Z, Chen C, Zhang X, Xie Y, Wu K, Mo Y, Chen J, and Shen S
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- Child, Infant, Humans, Antimetabolites, Antineoplastic, Prognosis, Risk Factors, Methotrexate, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma chemically induced
- Abstract
This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 μmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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5. Letter: Thioguanine, an underutilised option in inflammatory bowel disease?
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Chetwood JD, Paramsothy S, and Leong RW
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- Humans, Azathioprine therapeutic use, Antimetabolites, Antineoplastic, Mercaptopurine therapeutic use, Thioguanine therapeutic use, Inflammatory Bowel Diseases drug therapy
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- 2024
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6. VEXAS syndrome: complete molecular remission after hypomethylating therapy.
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Sockel K, Götze K, Ganster C, Bill M, Georgi JA, Balaian E, Aringer M, Trautmann-Grill K, Uhlig M, Bornhäuser M, Haase D, and Thiede C
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- Humans, Prospective Studies, Azacitidine, Pathologic Complete Response, Antimetabolites, Antineoplastic, Myelodysplastic Syndromes drug therapy, Skin Diseases, Genetic
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The VEXAS syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While various therapeutic strategies have been explored in case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation is considered the only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of the underlying UBA1 mutant clone outside the context of allogeneic HCT. Both patients received treatment with the hypomethylating agent azacitidine, and deep molecular remission triggered treatment de-escalation and even cessation with sustained molecular remission in one of them. Prospective studies are necessary to clarify which VEXAS patients will benefit most from hypomethylating therapy and to understand the variability in the response to different treatment strategies., (© 2024. The Author(s).)
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- 2024
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7. Development and validation of a model to predict acute kidney injury following high-dose methotrexate in patients with lymphoma.
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Rice ML, Barreto EF, Rule AD, Martin CE, Truong HL, Mara KC, Kashani KB, Thompson CA, Witzig TE, and Barreto JN
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- Adult, Humans, Male, Middle Aged, Methotrexate therapeutic use, Antimetabolites, Antineoplastic, Retrospective Studies, Acute Kidney Injury chemically induced, Acute Kidney Injury epidemiology, Acute Kidney Injury drug therapy, Lymphoma drug therapy
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Study Objective: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure., Design: Retrospective analysis., Setting: Multisite integrated health system throughout Minnesota and Wisconsin., Patients: Adult patients with lymphoma who received HDMTX as a 4-h infusion., Measurements and Main Results: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort., Conclusion: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma., (© 2023 Pharmacotherapy Publications, Inc.)
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- 2024
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8. Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing.
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Turner AJ, Haidar CE, Yang W, Boone EC, Offer SM, Empey PE, Haddad A, Tahir S, Scharer G, Broeckel U, and Gaedigk A
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- Child, Humans, Haplotypes, Antimetabolites, Antineoplastic, Pharmacogenomic Testing, Genotype, Dihydrouracil Dehydrogenase (NADP) metabolism, Population Health
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The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate-limiting enzyme for the metabolism of fluoropyrimidines 5-fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129-5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single-nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function-altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129-5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129-5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false-positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129-5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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9. Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: a systematic review.
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Yang Y, Liu Z, Chen J, Wang X, Jiao Z, and Wang Z
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- Adult, Infant, Infant, Newborn, Humans, Child, Methotrexate, Antimetabolites, Antineoplastic
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Purpose: To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition., Methods: We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles., Results: Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27-0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07-0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03-0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05-1.68) L/kg/h, and volume of distribution was 0.25 (0.018-0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8-35.3%, whereas those in others increased it by 15-48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients., Conclusions: Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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10. Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer
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Dongdong Luo, Xiaochun Liu, Leilei Jiang, Zhikun Guo, Yan Lv, Xiaochen Tian, Xiaoyan Wang, Shuxiang Cui, Shengbiao Wan, Xianjun Qu, Ximing Xu, and Xiaoyang Li
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Antimetabolites, Antineoplastic ,Drug Discovery ,Animals ,Molecular Medicine ,Fluorouracil ,Colorectal Neoplasms ,Sphingosine-1-Phosphate Receptors ,Dihydrouracil Dehydrogenase (NADP) - Abstract
Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound
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- 2022
11. Five‐day versus 7‐day treatment regimen with azacitidine in lower risk myelodysplastic syndrome: A phase 2, multicenter, randomized trial
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Silvia Park, So Yeon Park, Je‐Hwan Lee, Eun‐Ji Choi, Kyoo‐Hyung Lee, Sung‐Soo Yoon, Junshik Hong, Dong‐Yeop Shin, and Yoo‐Jin Kim
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Adult ,Antimetabolites, Antineoplastic ,Cancer Research ,Treatment Outcome ,Oncology ,Myelodysplastic Syndromes ,Azacitidine ,Humans ,Blood Transfusion ,Middle Aged ,Thrombocytopenia - Abstract
Low-dose azacitidine (AZA) regimens, primarily 5-day AZA, have been used in lower risk myelodysplastic syndrome (LrMDS) but they have yet to be directly compared to the standard 7-day, uninterrupted dosing schedule.In this phase 2, multicenter, randomized trial, 55 patients with adult LrMDS (low and intermediate-1 risk by international prognostic scoring system [IPSS]) were randomly assigned and received either 5-day (n = 26) or 7-day (n = 29) AZA between March 2012 and August 2020. The trial was stopped prematurely because of the slow accrual of patients. The primary end point was the overall response rate (ORR) of the 5-day AZA as compared to that of the 7-day regimen.Median patient age was 59 years, and IPSS intermediate-1 risk comprised the majority (81.8%). The median number of cycles in both arms was six. In the ITT subset (n = 53), in each of the 5-day and 7-day arms, the ORR of 48.0% and 39.3%, hematologic improvement of 44.0% and 39.3%, and RBC transfusion independence of 35.3% and 40.0% were observed respectively, and none of these findings were significantly different between the two arms. A cytogenetic response rate was significantly higher in the 7-day arm (8.3% and 53.8%, p = .027). Survival and adverse events were similar between the groups, although gastrointestinal toxicities, grade ≥3 thrombocytopenia, and febrile neutropenia were less frequent in the 5-day arm.The 5-day AZA in LrMDS showed comparable efficacy to a 7-day regimen in terms of similar overall response and other outcomes, despite significantly higher rates of cytogenetic responses in the 7-day regimen.Azacitidine (75 mg/m
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- 2022
12. Bone marrow fibrosis impact on response to azacitidine in myelodysplastic syndromes
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Roya Shahidi, Muhajir Mohamed, Archana Sharma, Jessica Heenan, Julia Gardner, and Sam Hitchins
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Antimetabolites, Antineoplastic ,Treatment Outcome ,Primary Myelofibrosis ,Myelodysplastic Syndromes ,Azacitidine ,Humans ,Prospective Studies ,Fibrosis ,Retrospective Studies ,Pathology and Forensic Medicine - Abstract
Bone marrow fibrosis in myelodysplastic syndromes (MDS) has been associated with poor outcome. However, these studies were conducted prior to the widespread use of azacitidine in the management of MDS. Our study aimed to assess whether treatment with azacitidine ameliorates the inferior outcome in MDS with fibrosis. A retrospective study of all patients diagnosed with MDS and treated with azacitidine over 3 years in two institutions was performed. A total of 21 patients were included in this study. Approximately half of these had moderate to severe bone marrow fibrosis at the start of treatment with azacitidine. The median overall survival was 34 months in patients with non-fibrotic bone marrow compared to 14 months in patients with fibrotic marrow (p=0.0007). Median event-free survival was 26 months versus 12 months (p=0.0027) in patients with non-fibrotic and fibrotic marrow, respectively. In multivariate analysis, bone marrow fibrosis was an independent factor in overall survival. Transfusion requirement was not different between the two groups. Despite the small sample size, we observed a worse outcome in azacitidine treated patients with MDS and fibrotic marrow. We suggest a prospective larger study to confirm the above finding.
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- 2022
13. Introducing a simple and cost-effective RT-PCR protocol for detection of DPYD*2A polymorphism: the first study in Kurdish population
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Mohammad Salmani, Bayazid Ghaderi, Alan Fotoohi, Ramtin Omid-Shafa’at, Zakaria Vahabzadeh, Omid Fotouhi, and Mohammad Abdi
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Pharmacology ,Antimetabolites, Antineoplastic ,Cancer Research ,Dihydropyrimidine Dehydrogenase Deficiency ,Drug-Related Side Effects and Adverse Reactions ,Oncology ,Reverse Transcriptase Polymerase Chain Reaction ,Cost-Benefit Analysis ,Humans ,Pharmacology (medical) ,Fluorouracil ,Toxicology ,Dihydrouracil Dehydrogenase (NADP) - Abstract
Fluoropyrimidines, the major chemotherapeutic agents in various malignancies treatment, are metabolized by dihydropyrimidine dehydrogenase (DPD). DPD deficiency can lead to severe and sometimes fatal toxicity. In the present study, we developed a simple protocol to detect the DPYD*2A variant. Common side effects in patients treated with these drugs were also evaluated in a Kurdish population.We established a reverse-transcriptase polymerase chain reaction (RT-PCR) technique for detection of DPYD*2A. Sanger sequencing was used to confirm the results. 121 Kurdish patients receiving fluoropyrimidine derivatives were enrolled, and clinical information regarding the dosage and toxicity was analyzed.Our RT-PCR method was able to detect one patient with heterozygous state for DPYD*2A (0.8%). The most observed adverse drug reactions were tingling, nausea, and hair loss. The frequency of patients with the toxicity of grade 3 or worse was 6.6%.This was the first study that detect DPYD*2A polymorphism in the Kurdish population. Our method was successfully able to detect the DPYD*2A variant and, due to its simplicity and cost-effectiveness, it may be considered as an alternative to the current methods, especially in developing countries. Our detected polymorphism rate at 0.8% is comparable with other studies. Despite the low rate of DPYD*2A polymorphism, pharmacogenetics assessment before beginning the treatment process is highly recommended due to its association with a high risk of severe toxicity.
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- 2022
14. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML
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Lionel Adès, Larisa Girshova, Vadim A. Doronin, María Díez-Campelo, David Valcárcel, Suman Kambhampati, Nora-Athina Viniou, Dariusz Woszczyk, Raquel De Paz Arias, Argiris Symeonidis, Achilles Anagnostopoulos, Eduardo Ciliao Munhoz, Uwe Platzbecker, Valeria Santini, Robert J. Fram, Ying Yuan, Sharon Friedlander, Douglas V. Faller, Mikkael A. Sekeres, Institut Català de la Salut, [Adès L] INSERM U944, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Louis and University of Paris, Paris, France. [Girshova L] Federal Almazov North-West Medical Research Centre, Saint-Petersburg, Russia. [Doronin VA] City Clinical Hospital 40, Moscow, Russia. [Díez-Campelo M] Institute for Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, Salamanca, Spain. [Valcárcel D] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d'Hematologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Kambhampati S] Sarah Cannon at Research Medical Center, Kansas City, MO, and Vall d'Hebron Barcelona Hospital Campus
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acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::antimetabolitos::antimetabolitos antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,Antimetabolites, Antineoplastic ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Antimetabolites::Antimetabolites, Antineoplastic [CHEMICALS AND DRUGS] ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Leukemia, Myelomonocytic, Chronic ,neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mielomonocítica crónica [ENFERMEDADES] ,Cyclopentanes ,Hematology ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores] ,Quimioteràpia combinada ,Medicaments antineoplàstics - Efectes secundaris ,Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myelomonocytic, Chronic [DISEASES] ,Pyrimidines ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Leucèmia mieloide aguda - Tractament ,Other subheadings::Other subheadings::/adverse effects [Other subheadings] ,Azacitidine ,Humans ,Drug Therapy, Combination - Abstract
Pevonedistat; Chronic myelomonocytic leukemia Pevonedistat; Leucemia mielomonocítica crónica Pevonedistat; Leucèmia mielomonocítica crònica PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954. This study was sponsored by Takeda Development Centers Inc (TDCA; Lexington, MA).
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- 2022
15. Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits, and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes
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Amer M. Zeidan, Namita Joshi, Hrishikesh Kale, Wei-Jhih Wang, Shelby Corman, Tehseen Salimi, and Robert S. Epstein
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Antimetabolites, Antineoplastic ,Cancer Research ,Hematology ,DNA Methylation ,Decitabine ,Medicare ,Hospitals ,United States ,Treatment Outcome ,Oncology ,Myelodysplastic Syndromes ,Azacitidine ,Humans ,Emergency Service, Hospital ,Aged - Abstract
Previous analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy.We used the 2010-2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles.Overall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P.001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation.An increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.
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- 2022
16. Prospective comparison of outcomes with azacitidine and decitabine in patients with AML ineligible for intensive chemotherapy
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Amer M. Zeidan, Pierre Fenaux, Marco Gobbi, Jiří Mayer, Gail J. Roboz, Jürgen Krauter, Tadeusz Robak, Hagop M. Kantarjian, Jan Novák, Wieslaw W. Jedrzejczak, Xavier Thomas, Mario Ojeda-Uribe, Yasushi Miyazaki, Yoo Hong Min, Su-Peng Yeh, Joseph M. Brandwein, Liana Gercheva, Judit Demeter, Elizabeth A. Griffiths, Karen W. L. Yee, Jean-Pierre J. Issa, Jan Philipp Bewersdorf, Harold Keer, Yong Hao, Mohammad Azab, and Hartmut Döhner
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Antimetabolites, Antineoplastic ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Immunology ,Azacitidine ,Humans ,Cell Biology ,Hematology ,Decitabine ,Biochemistry - Published
- 2022
17. Effect of a Novel Soaking Solution Used in Patients With Hand-Foot Syndrome as a Result of Capecitabine Treatment: A Randomized and Self-Controlled Trial
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Yuxiu Xie, Qiong Wang, Ting Hu, Renwang Chen, Jue Wang, Haiyan Chang, Xin Peng, and Jing Cheng
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Antimetabolites, Antineoplastic ,Cancer Research ,Oncology ,Quality of Life ,Humans ,Breast Neoplasms ,Female ,Hand-Foot Syndrome ,Fluorouracil ,Capecitabine - Abstract
Hand-foot syndrome (HFS) is a common adverse event in patients receiving capecitabine therapy for breast cancer, and the symptoms of HFS significantly impair patient quality of life. However, currently there are no effective drugs or measures to prevent and alleviate the occurrence of HFS.To assess the effectiveness of a novel soaking solution, a mixture solution of dexamethasone, gentamicin and vitamin B12, in patients with grade 2-3 HFS after capecitabine treatment for breast cancer.Patients with grade 2-3 HFS according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) were enrolled in this randomized, single-center, self-controlled trial. Each patient's right and left hands or feet were individually randomized to soak in either a novel soaking solution (treated hands or feet) or a placebo liquid (control hands or feet) for three times a day, each time for 15 minutes and for four weeks. Effectiveness was evaluated according to CTCAE grades, defined as a reduction of 1 or more CTCAE grades.A total of 60 patients were enrolled. The HFS CTCAE grade of the treated hands and feet at 4 weeks of HFS treatment was significantly decreased compared to that of the control hands and feet (P = .005). Significant differences were also observed between the treatment conditions in terms of the HFS effectiveness rate: treated group 80% and placebo group 51.7% (P = .001). No adverse or unexpected events were observed during the whole trial.Soaking affected hands or feet in a novel soaking solution safely and effectively reduced the severity of HFS following treatment with capecitabine for breast cancer.
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- 2022
18. Survey of US Medical Oncologists' Practices and Beliefs Regarding
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Kyoin, Koo, Amy L, Pasternak, N Lynn, Henry, Vaibhav, Sahai, and Daniel L, Hertz
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Oncologists ,Antimetabolites, Antineoplastic ,Dihydropyrimidine Dehydrogenase Deficiency ,Humans ,Breast Neoplasms ,Female ,Fluorouracil ,ORIGINAL CONTRIBUTIONS ,Capecitabine ,Dihydrouracil Dehydrogenase (NADP) - Abstract
PURPOSE: Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing. METHODS: Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses. RESULTS: Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%). CONCLUSION: Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines.
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- 2023
19. Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront <scp> DPYD </scp> Genotyping
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Cassandra White, Rodney J. Scott, Christine Paul, Andrew Ziolkowski, David Mossman, Stephen B. Fox, Michael Michael, and Stephen Ackland
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Pharmacology ,Antimetabolites, Antineoplastic ,Dihydropyrimidine Dehydrogenase Deficiency ,Genotype ,Humans ,Pharmacology (medical) ,Fluorouracil ,Prospective Studies ,Dihydrouracil Dehydrogenase (NADP) - Abstract
Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.
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- 2022
20. Hypersensitivity reaction to high-dose methotrexate and methotrexate-induced acral erythema in a child with acute lymphoblastic leukemia
- Author
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Mitsuko, Akaihata, Kenji, Miyata, Yasuto, Shimomura, Toshinori, Hori, and Akihisa, Okumura
- Subjects
Male ,Pharmacology ,Antimetabolites, Antineoplastic ,Methotrexate ,Erythema ,Hypersensitivity ,Humans ,Pharmacology (medical) ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Child - Abstract
A 9-year-old boy with acute lymphoblastic leukemia experienced a hypersensitivity reaction (HSR) and acral erythema upon receiving high-dose methotrexate (HDMTX). Both HSR and acral erythema are uncommon adverse events of MTX therapy, and MTX has not been reported to cause HSRs in specific ethnic groups. We assessed the severity of each symptom and were successful in managing these adverse events for continuing subsequent HDMTX therapies. HSR appeared during the first and second HDMTX courses. Acral erythema occurred after the second and fourth courses. Desensitization by reducing the infusion rate and premedication allowed the continuation of HDMTX. Acral erythema improved with supportive care without dose reduction or interval lengthening. HSRs to MTX should be considered even during the first course. MTX-induced acral erythema is a self-limited reaction; therefore, the chemotherapeutic regimen should not be modified unless necessary.
- Published
- 2022
21. Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies
- Author
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C.L. Beach, Hartmut Döhner, Valeria Santini, Andrew H. Wei, Ignazia La Torre, Guillermo Garcia-Manero, and Barry Skikne
- Subjects
Adult ,Oncology ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,law.invention ,Maintenance therapy ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,media_common.cataloged_instance ,European union ,neoplasms ,Randomized Controlled Trials as Topic ,media_common ,Myeloproliferative Disorders ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Hematology ,medicine.disease ,Clinical trial ,Leukemia, Myeloid, Acute ,stomatognathic diseases ,Clinical Trials, Phase III as Topic ,Hypomethylating agent ,Myelodysplastic Syndromes ,Azacitidine ,business - Abstract
Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials.
- Published
- 2022
22. Population Pharmacokinetics of Oral Azacitidine, and Exposure-Response Analysis in Acute Myeloid Leukemia.
- Author
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Gaudy A, Laille E, Bailey R, Zhou S, Skikne B, and Beach CL
- Subjects
- Adult, Humans, Antimetabolites, Antimetabolites, Antineoplastic, Azacitidine adverse effects, Clinical Trials, Phase III as Topic, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myelomonocytic, Chronic chemically induced, Leukemia, Myelomonocytic, Chronic drug therapy, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes chemically induced
- Abstract
Oral azacitidine (oral-AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post-intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral-AZA concentration-time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK-estimated exposure parameters were used to evaluate exposure-response relationships in the phase III QUAZAR AML-001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral-AZA concentration records. The final PopPK model was a one-compartment model with first-order absorption incorporating an absorption lag time and first-order elimination. Regression analyses identified two oral-AZA exposure parameters (area under the plasma concentration-time curve at steady state (AUC
ss ); maximum plasma concentration (Cmax )) as statistically significant predictors for relapse-free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUCss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUCss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73-12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76-4.44, P < 0.001), and Cmax at steady-state (OR = 2.38, 95% CI = 1.23-4.76, P = 0.012). A decreasing trend was identified between AUCss and relapse-related schedule extensions, vs. an increasing trend between AUCss and event-related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral-AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk., (© 2023 Bristol Myers Squibb. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2023
- Full Text
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23. Management of a complete hydatidiform mole with a coexisting live fetus followed by successful treatment of maternal metastatic gestational trophoblastic disease: learning points
- Author
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Swee Lin Yip, Khurshid Merchant, and Zhun Wei Mok
- Subjects
Adult ,Male ,medicine.medical_specialty ,Down syndrome ,Antimetabolites, Antineoplastic ,Lung Neoplasms ,medicine.medical_treatment ,Case Report ,03 medical and health sciences ,0302 clinical medicine ,Obstetrics and gynaecology ,Breech presentation ,Pregnancy ,Placenta ,medicine ,Humans ,Gestational Trophoblastic Disease ,reproductive and urinary physiology ,Chemotherapy ,030219 obstetrics & reproductive medicine ,Obstetrics ,Gestational trophoblastic disease ,business.industry ,Infant, Newborn ,General Medicine ,Hydatidiform Mole ,medicine.disease ,medicine.anatomical_structure ,Methotrexate ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,business ,medicine.drug - Abstract
A 34-year-old patient had her first trimester Down syndrome scan followed by serial ultrasound scans which showed a single intrauterine pregnancy with multiple cystic areas in the anterior placenta. She presented in preterm labour with a breech presentation at 32 weeks and underwent an emergency caesarean section. She delivered a male infant weighing 1750 g. The placental histopathology showed a complete hyatidiform mole. At 4 weeks postpartum, beta-human chorionic gonadotrophin (Bhcg) levels rose from 460 to 836 mIU/mL over 1 week. Metastatic workup revealed prominent pelvic nodes and pulmonary nodules in both lungs. This was discussed at the Multi-Disciplinary Tumour Board and single-agent intramuscular methotrexate was recommended. After chemotherapy, she achieved Bhcg normalisation after three cycles. This case highlights the importance of clinical vigilance even in low-risk patients. Unexpected findings on ultrasound should involve multidisciplinary input with radiology colleagues. A high index of suspicion for gestational trophoblastic disease and close follow-up is imperative.
- Published
- 2023
24. Chidamide and Decitabine in Combination with a HAG Priming Regimen for Acute Myeloid Leukemia with TP53 Mutation
- Author
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Bei, Zhang, Zhixin, Pei, Hongxia, Wang, Huimin, Wu, Junjie, Wang, Junjun, Bai, and Qinglin, Song
- Subjects
Adult ,Male ,Antimetabolites, Antineoplastic ,HAG ,Remission Induction ,Cytarabine ,TP53 mutation ,Aminopyridines ,Middle Aged ,acute myeloid leukemia ,Leukemia, Myeloid, Acute ,Treatment Outcome ,chidamide ,Benzamides ,Granulocyte Colony-Stimulating Factor ,Mutation ,Humans ,Female ,Tumor Suppressor Protein p53 ,Homoharringtonine ,decitabine ,Aged ,Retrospective Studies - Abstract
We analyzed the treatment effects of chidamide and decitabine in combination with a HAG (homoharringtonine, cytarabine, G-CSF) priming regimen (CDHAG) in acute myeloid leukemia (AML) patients with TP53 mutation. Seven TP53 mutated AML patients were treated with CDHAG. The treatment effects were assessed using hemogram detection and bone marrow aspirate. The possible side effects were evaluated based on both hematological and non-hematological toxicity. Four of the seven patients were classified as having achieved complete remission after CDHAG treatment; one patient was considered to have achieved partial remission, and the remaining two patients were considered in non-remission. The overall response rate (ORR) to CDHAG was 71.4%. Regarding the side effects, the hematological toxicity level of the seven patients ranged from level III to level IV, and infections that occurred at lung, blood, and skin were recorded. Nausea, vomiting, liver injury, and kidney injury were also detected. However, all side effects were attenuated by proper management. The CDHAG regimen clearly improved the ORR (71.4%) of TP53-mutated AML patients, with no severe side effects.
- Published
- 2022
25. Effect of the Proton Pump Inhibitor Esomeprazole on the Systemic Exposure of Capecitabine
- Author
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Peter de Bruijn, Sander Bins, Ferry A.L.M. Eskens, Femke M. de Man, Ron H.J. Mathijssen, Niels Heersche, Esther Oomen-de Hoop, Leni van Doorn, Ivo Bijl, Ate van der Gaast, and Medical Oncology
- Subjects
Male ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,medicine.drug_class ,Biological Availability ,Proton-pump inhibitor ,Carbonated Beverages ,Gastroenterology ,Esomeprazole ,Capecitabine ,Pharmacokinetics ,SDG 3 - Good Health and Well-being ,Neoplasms ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Drug Interactions ,Pharmacology (medical) ,Prospective Studies ,Netherlands ,Pharmacology ,Cross-Over Studies ,business.industry ,Proton Pump Inhibitors ,Middle Aged ,Drug interaction ,Crossover study ,Treatment Outcome ,Concomitant ,Female ,Drug Monitoring ,business ,medicine.drug - Abstract
Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) −10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI −16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.
- Published
- 2022
26. Effect of Thymidine Phosphorylase Gene Demethylation on Sensitivity to 5-Fluorouracil in Colorectal Cancer Cells
- Author
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Muneyuki, Koyama, Erika, Osada, Nubutake, Akiyama, Ken, Eto, and Yoshinobu, Manome
- Subjects
Antimetabolites, Antineoplastic ,Thymidine Phosphorylase ,Cancer Research ,Transcription, Genetic ,Cell Survival ,General Medicine ,Decitabine ,Demethylation ,Oncology ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Humans ,Fluorouracil ,Colorectal Neoplasms - Abstract
Chemotherapy is used for recurrent and metastatic colorectal cancer, but the response rate of 5-fluorouracil (5-FU), the standard treatment for colorectal cancer, is low. We hypothesized that thymidine phosphorylase (TYMP) expression, a rate-limiting activating enzyme of 5-FU, is regulated by methylation of the gene promoter region, and demethylation of TYMP would increase sensitivity to 5-FU.HCT116 colon cancer cells were treated with 5-aza-2'-deoxycytidine, a demethylating agent, and changes in TYMP transcription and sensitivity to 5-FU were evaluated.TYMP expression increased over 54-fold in HCT116 transfected with TYMP. The cytotoxicity of 5-FU increased up to 5.5-fold. In comparison, in HCT116 treated with 5-aza-2'-deoxycytidine, TYMP expression increased 5.8-fold. However, the cytotoxicity of 5-FU remained unchanged.Demethylating agent alone did not promote the cytotoxicity of 5-FU against colorectal cancer. To further increase the sensitivity to 5-FU, combination with adjuvant therapy focusing on metabolic pathways other than the TYMP pathway appear necessary.
- Published
- 2022
27. Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model
- Author
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YUSUKE AOKI, YASUNORI TOME, QINGHONG HAN, JUN YAMAMOTO, KAZUYUKI HAMADA, NORIYUKI MASAKI, YUTARO KUBOTA, MICHAEL BOUVET, KOTARO NISHIDA, and ROBERT M. HOFFMAN
- Subjects
Antimetabolites, Antineoplastic ,Osteosarcoma ,Cancer Research ,Administration, Oral ,Mice, Nude ,Bone Neoplasms ,General Medicine ,Xenograft Model Antitumor Assays ,Tumor Burden ,Carbon-Sulfur Lyases ,Disease Models, Animal ,Mice ,Methotrexate ,Treatment Outcome ,Oncology ,Drug Resistance, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans - Abstract
Osteosarcoma is the most common bone sarcoma. Although surgery and chemotherapy are initially effective, the 5-year survival is approximately 60% to 80%, and has not improved over three decades. We have previously shown that methionine restriction (MR) induced by oral recombinant methioninase (o-rMETase), is effective against osteosarcoma in patient-derived orthotopic xenograft (PDOX) nude-mouse models. In the present report, the efficacy of the combination of oral o-rMETase and methotrexate (MTX) was examined in an osteosarcoma PDOX mouse model.An osteosarcoma-PDOX model was previously established by implanting tumor fragments into the proximal tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups: control; o-rMETase alone; MTX alone; combination of o-rMETase and MTX. The mice were sacrificed after 4 weeks of treatment.The combination of o-rMETase and MTX showed significantly higher efficacy compared to the control group (p=0.04). The combination also showed significantly higher efficacy compared to MTX alone (p=0.04). No significant efficacy of o-rMETase alone or MTX alone compared to control was shown (p=0.21, 1.00, respectively). Only the combination of o-rMETase and MTX reduced the cancer-cell density in the osteosarcoma tumor.rMETase converted an osteosarcoma PDOX from MTX-resistant to MTX-sensitive and thereby shows future clinical potential.
- Published
- 2022
28. Methionine Restriction: Ready for Prime Time in the Cancer Clinic?
- Author
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Jun, Yamamoto, Qinghong, Han, Mark, Simon, Daniel, Thomas, and Robert M, Hoffman
- Subjects
Antimetabolites, Antineoplastic ,Carbon-Sulfur Lyases ,Cancer Research ,Methionine ,Oncology ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Diet, Protein-Restricted ,Animals ,Humans ,General Medicine - Abstract
Attempts to selectively starve cancers in the clinic have been made at least since the time of Warburg beginning 100 years ago. Calorie-restriction or low-carbohydrate diets have had limited success with cancer patients. Methionine restriction is another strategy to selectively starve cancer cells, since cancers are addicted to methionine, unlike normal cells. Methionine addiction of cancer is termed the Hoffman effect. Numerous preclinical studies over the past half century have shown methionine restriction to be highly effective against all major cancer types and synergistic with chemotherapy. Low-methionine medical diets can be effective in lowering methionine and have shown some clinical promise, but they are not palatable and thereby not sustainable. However, selectively choosing among plant-based foods allows a variety of low-methionine diets that are sustainable. Our laboratory has developed a methioninase that can be administered orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer, including hormone-independent prostate cancer, and other recalcitrant cancers. The question is whether methionine restriction through a low-methionine diet, or even greater methionine restriction with methioninase in combination with a low-methionine diet, is ready for prime time in the clinic, especially in combination with other synergistic therapy. The question will hopefully be answered in the near future, especially for advanced cancer patients who have failed all standard therapy.
- Published
- 2022
29. Azacitidine, intensive chemotherapy or best supportive care in relapsed or refractory acute myeloid leukemia, a DATAML registry study
- Author
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Noémie Gadaud, Harmony Leroy, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Sophie Dimicoli-Salazar, Jean-Baptiste Rieu, Isabelle Luquet, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Pierre Bories, Arnaud Pigneux, Christian Récher, Pierre-Yves Dumas, and Sarah Bertoli
- Subjects
Antimetabolites, Antineoplastic ,Leukemia, Myeloid, Acute ,Cancer Research ,Treatment Outcome ,Oncology ,Chronic Disease ,Azacitidine ,Humans ,Registries ,Hematology - Abstract
We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (
- Published
- 2022
30. Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients
- Author
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Grimm, Juliane, Simnica, Donjete, Jäkel, Nadja, Paschold, Lisa, Willscher, Edith, Schulze, Susann, Dierks, Christine, Al-Ali, Haifa Kathrin, and Binder, Mascha
- Subjects
Aged, 80 and over ,Male ,Antimetabolites, Antineoplastic ,T-Lymphocytes ,Immunosurveillance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Middle Aged ,Survival Analysis ,Article ,Acute myeloid leukaemia ,Leukemia, Myeloid, Acute ,Bone Marrow ,Azacitidine ,Humans ,T-cell receptor ,Female ,RC254-282 ,Aged - Abstract
Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML. Trial registration: DRKS identifier: DRKS00004519
- Published
- 2022
31. Prospective evaluation of high‐dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function
- Author
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Andrew D. Rule, Kianoush Kashani, Carrie A. Thompson, Joel M. Reid, Thomas E. Witzig, Nelson Leung, Renee M. McGovern, Kristin C. Mara, Erin F. Barreto, Thomas R. Larson, and Jason N. Barreto
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Lymphoma ,Population ,Urology ,Renal function ,RM1-950 ,Kidney Function Tests ,General Biochemistry, Genetics and Molecular Biology ,Article ,chemistry.chemical_compound ,Pharmacokinetics ,Interquartile range ,medicine ,Humans ,Prospective Studies ,General Pharmacology, Toxicology and Pharmaceutics ,education ,Aged ,education.field_of_study ,Creatinine ,business.industry ,General Neuroscience ,Research ,Area under the curve ,General Medicine ,Articles ,Middle Aged ,Methotrexate ,chemistry ,Female ,Liver function ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,business ,medicine.drug ,Glomerular Filtration Rate - Abstract
High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.
- Published
- 2022
32. Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis
- Author
-
Sweta Ghosh, Rajbir Singh, Zachary Matthew Vanwinkle, Haixun Guo, Praveen Kumar Vemula, Ajay Goel, Bodduluri Haribabu, and Venkatakrishna Rao Jala
- Subjects
Antimetabolites, Antineoplastic ,Forkhead Box Protein M1 ,Forkhead Box Protein O3 ,Azoxymethane ,Medicine (miscellaneous) ,Gastrointestinal Microbiome ,Neoplasm Proteins ,Mice ,Coumarins ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Colonic Neoplasms ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,Humans ,Fluorouracil ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Abstract
The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers.
- Published
- 2022
33. Coculture in vitro with endothelial cells induces cytarabine resistance of acute myeloid leukemia cells in a VEGF-A/VEGFR-2 signaling–independent manner
- Author
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Akira Yamauchi, Keisuke Kitakaze, Shuichiro Okamoto, Kei Miyano, Hitomi Kato, Mizuho Kajikawa, Momoe Itsumi, Chikage Kawai, and Futoshi Kuribayashi
- Subjects
Vascular Endothelial Growth Factor A ,Antimetabolites, Antineoplastic ,Indoles ,Biophysics ,Angiogenesis Inhibitors ,HL-60 Cells ,Models, Biological ,Biochemistry ,Cell Line ,Gene Knockout Techniques ,Jurkat Cells ,Paracrine signalling ,Cell Movement ,medicine ,Humans ,Phosphorylation ,Molecular Biology ,Neovascularization, Pathologic ,Gene Expression Regulation, Leukemic ,Chemistry ,Cell Cycle ,Cytarabine ,Endothelial Cells ,Myeloid leukemia ,U937 Cells ,Cell Biology ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Coculture Techniques ,Endothelial stem cell ,Leukemia, Myeloid, Acute ,Vascular endothelial growth factor A ,Leukemia ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,Apoptosis ,Cancer research ,Bone marrow ,K562 Cells ,Signal Transduction ,medicine.drug - Abstract
An interaction between acute myeloid leukemia (AML) cells and endothelial cells in the bone marrow seems to play a critical role in chemosensitivity on leukemia treatment. The endothelial niche reportedly enhances the paracrine action of the soluble secretory proteins responsible for chemoresistance in a vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway–dependent manner. To further investigate the contribution of VEGF-A/VEGFR-2 signaling to the chemoresistance of AML cells, a biochemical assay system in which the AML cells were cocultured with human endothelial EA.hy926 cells in a monolayer was developed. By coculture with EA.hy926 cells, this study revealed that the AML cells resisted apoptosis induced by the anticancer drug cytarabine. SU4312, a VEGFR-2 inhibitor, attenuated VEGFR-2 phosphorylation and VEGF-A/VEGFR-2 signaling–dependent endothelial cell migration; thus, this inhibitor was observed to block VEGF-A/VEGFR-2 signaling. Interestingly, this inhibitor did not reverse the chemoresistance. When VEGFR-2 was knocked out in EA.hy926 cells using the CRISPR–Cas9 system, the cytarabine-induced apoptosis of AML cells did not significantly change compared with that of wild-type cells. Thus, coculture-induced chemoresistance appears to be independent of VEGF-A/VEGFR-2 signaling. When the transwell, a coculturing device, separated the AML cells from the EA.hy926 cells in a monolayer, the coculture-induced chemoresistance was inhibited. Given that the migration of VEGF-A/VEGFR-2 signaling–dependent endothelial cells is necessary for the endothelial niche formation in the bone marrow, VEGF-A/VEGFR-2 signaling contributes to chemoresistance by mediating the niche formation process, but not to the chemoresistance of AML cells in the niche.
- Published
- 2022
34. Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine
- Author
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Theodora Chatzisideri, George Leonidis, Theodoros Karampelas, Eleni Skavatsou, Angeliki Velentza-Almpani, Francesca Bianchini, Constantin Tamvakopoulos, and Vasiliki Sarli
- Subjects
Antimetabolites, Antineoplastic ,Integrins ,Lung Neoplasms ,Deoxycytidine ,Peptides, Cyclic ,Gemcitabine ,Mice, Inbred C57BL ,Mice ,A549 Cells ,Integrin, c(RGDyK)-based conjugates, gemcitabine, Targeted Cancer Therapy ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Cell Proliferation - Abstract
c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin α
- Published
- 2021
35. Hemoglobin is a key determinant of quality of life before and during azacitidine-based therapy for myelodysplasia and low blast count acute myeloid leukemia
- Author
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Zoe K, McQuilten, Ljoudmila, Busija, John F, Seymour, Simon, Stanworth, Erica M, Wood, Melita, Kenealy, and Robert, Weinkove
- Subjects
Antimetabolites, Antineoplastic ,Hemoglobins ,Leukemia, Myeloid, Acute ,Cancer Research ,Dyspnea ,Oncology ,Myelodysplastic Syndromes ,Azacitidine ,Quality of Life ,Humans ,Hematology ,Fatigue ,Aged - Abstract
Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a
- Published
- 2021
36. Oral hypomethylating agents: beyond convenience in MDS
- Author
-
Elizabeth A, Griffiths
- Subjects
Antimetabolites, Antineoplastic ,MDS: Beyond a One-Size-Fits-All Approach ,Myelodysplastic Syndromes ,Azacitidine ,Quality of Life ,Administration, Oral ,Humans ,Female ,Hematology ,Decitabine ,Uridine ,Aged - Abstract
Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.
- Published
- 2021
37. High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial
- Author
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R. Spencer Tong, Robert B. Gerbing, Todd A. Alonzo, Jeffrey W. Taub, Jim Wang, Lisa Eidenschink Brodersen, Reuven J. Schore, Maureen M. O'Brien, Amy Heerema-McKenney, Jason N. Berman, Shelton A Viola, Michael R. Loken, E. Anders Kolb, Betsy A. Hirsch, Alan S. Gamis, Karen M. Chisholm, Susana C. Raimondi, Nobuko Hijiya, Amy Beckman, Johann Hitzler, and Todd E. Druley
- Subjects
Male ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Down syndrome ,Neoplasm, Residual ,medicine.medical_treatment ,Immunology ,Biochemistry ,Gastroenterology ,Cog ,Internal medicine ,medicine ,Humans ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Cytarabine ,Infant ,Myeloid leukemia ,Cell Biology ,Hematology ,Prognosis ,Interim analysis ,medicine.disease ,Confidence interval ,Young age ,Treatment Outcome ,Leukemia, Myeloid ,Child, Preschool ,Female ,Down Syndrome ,business ,medicine.drug - Abstract
Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children’s Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (
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- 2021
38. Current Perspectives on the Role of Nrf2 in 5-Fluorouracil Resistance in Colorectal Cancer
- Author
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Jiayi Gong and Huaxi Xu
- Subjects
Pharmacology ,Antimetabolites, Antineoplastic ,Cancer Research ,Resistance (ecology) ,NF-E2-Related Factor 2 ,Mechanism (biology) ,Colorectal cancer ,business.industry ,medicine.drug_class ,Master regulator ,medicine.disease ,Cellular defense ,Antimetabolite ,Drug Resistance, Neoplasm ,Fluorouracil ,Cancer research ,medicine ,Humans ,Molecular Medicine ,Effective treatment ,Colorectal Neoplasms ,business ,Cell Proliferation ,medicine.drug - Abstract
Background: The antimetabolite, 5-Fluorouracil (5-FU), is the only chemotherapeutic drug to significantly improve 12-month survival rates of patients with Colorectal Cancer (CRC). However, resistance to 5-FU is a major obstacle to effective treatment. The mechanism of 5-FU resistance has been discovered but is not fully known. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of cellular defense against oxidative and electrophilic stresses, is considered a major factor in 5-FU resistance. Objective: The current study was conducted to discuss the role and mechanisms of Nrf2 in 5-FU resistance and to search for medicines or compounds that can reverse Nrf2-mediated 5-FU resistance. Methods: Literature was obtained by defining specific search terms and searching several databases. Results: Previous study suggested that overactivation of Nrf2 contributed to 5-FU resistance by regulating many cytoprotective genes. Interestingly, several medicines and compounds can repress 5-FU resistance mediated of Nrf2. Conclusion: This review describes the major 5-FU-resistance mechanisms of Nrf2 and summarizes the medicines/ compounds that can overcome them.
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- 2021
39. Secondary basophilic leukemia in Ph-negative myeloid neoplasms: A distinct subset with poor prognosis
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Philipp B. Staber, Peter Bettelheim, Christian Sillaber, Gabriele Stefanzl, Dubravka Smiljkovic, Daniela Berger, Georg Greiner, Peter Valent, Karin Bauer, Wolfgang R. Sperr, Ana-Iris Schiefer, Susanne Gamperl, Ilse Schwarzinger, Renate Thalhammer, Gregor Hoermann, Paul Knöbl, and Christoph Kornauth
- Subjects
Male ,Antimetabolites, Antineoplastic ,Original article ,Cancer Research ,Myeloid ,Azacitidine ,chemical and pharmacologic phenomena ,Venetoclax ,chemistry.chemical_compound ,parasitic diseases ,medicine ,Humans ,IgE receptor ,Myeloproliferative neoplasm ,RC254-282 ,Aged ,Aged, 80 and over ,Acute leukemia ,Leukemia ,Myeloproliferative Disorders ,business.industry ,Myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Neoplasms, Second Primary ,hemic and immune systems ,Prognosis ,medicine.disease ,Basophilic leukemia ,Basophils ,Basophilia ,medicine.anatomical_structure ,chemistry ,Myelodysplastic Syndromes ,Cancer research ,Female ,business ,medicine.drug - Abstract
During progression of myeloid neoplasms, the basophil compartment may expand substantially and in some of these patients, a basophilic leukemia is diagnosed. In patients with Ph-chromosome+ chronic myeloid leukemia, acceleration of disease is typically accompanied by marked basophilia. In other myeloid neoplasms, secondary leukemic expansion of basophils is rarely seen. We report on 5 patients who suffered from a myelodysplastic syndrome, myeloproliferative neoplasm, or acute leukemia and developed a massive expansion of basophils during disease progression. In 4 of 5 patients, peripheral blood basophil counts reached 40%, and the diagnosis “secondary basophilic leukemia” was established. As assessed by flow cytometry, neoplastic basophils expressed CD9, CD18, CD25, CD33, CD63, PD-L1, CD123, and CLL-1. In addition, basophils were found to display BB1 (basogranulin), 2D7, tryptase and KIT. In 4 of 5 patients the disease progressed quickly and treatment with azacitidine was started. However, azacitidine did not induce major clinical responses, and all patients died from progressive disease within 3 Y. In in vitro experiments, the patients´ cells and the basophilic leukemia cell line KU812 showed variable responses to targeted drugs, including azacitidine, venetoclax, hydroxyurea, and cytarabine. A combination of venetoclax and azacitidine induced cooperative antineoplastic effects in these cells. Together, secondary basophilic leukemia has a poor prognosis and monotherapy with azacitidine is not sufficient to keep the disease under control for longer time-periods. Whether drug combination, such as venetoclax+azacitidine, can induce better outcomes in these patients remains to be determined in future clinical studies.
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- 2021
40. Near Miss or Standard of Care? DPYD Screening for Cancer Patients Receiving Fluorouracil
- Author
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Lauren E Winquist, Eric Winquist, Richard B. Kim, and Michael Sanatani
- Subjects
Oncology ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Near Miss, Healthcare ,Case Report ,fluoropyrimidines ,030226 pharmacology & pharmacy ,Capecitabine ,03 medical and health sciences ,single nucleotide polymorphisms ,0302 clinical medicine ,Pharmacotherapy ,Internal medicine ,Neoplasms ,medicine ,Dihydropyrimidine dehydrogenase ,Humans ,cancer ,Dosing ,Adverse effect ,Dihydrouracil Dehydrogenase (NADP) ,Early Detection of Cancer ,RC254-282 ,Cancer ,business.industry ,Adverse effects ,dihydropyrimidine dehydrogenase ,Fluoropyrimidines ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Standard of Care ,Single nucleotide polymorphisms ,medicine.disease ,drug therapy ,Fluorouracil ,030220 oncology & carcinogenesis ,adverse effects ,DPYD ,Drug therapy ,business ,medicine.drug - Abstract
5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes.
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- 2021
41. Protective effects of melatonin and l-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes
- Author
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Asser I. Ghoneim, Lamiaa A Khatab, and Ihab T. Abdel-Raheem
- Subjects
Male ,Antimetabolites, Antineoplastic ,Anti-Inflammatory Agents ,Apoptosis ,Pharmacology ,Antioxidants ,Nitric oxide ,Rats, Sprague-Dawley ,Melatonin ,Lipid peroxidation ,chemistry.chemical_compound ,Carnitine ,medicine ,Animals ,General Medicine ,Glutathione ,Rats ,Methotrexate ,chemistry ,Toxicity ,Hepatocytes ,Trypan blue ,Chemical and Drug Induced Liver Injury ,medicine.drug - Abstract
The present study was designed to evaluate the possible protective effects of melatonin (MEL) and/or L-carnitine (L-CAR) against methotrexate (MTX)-induced toxicity in isolated rat hepatocytes. Hepatocytes were prepared using collagenase techniques of perfusion and digestion of rat liver. Trypan blue uptake, as well as, glutathione (GSH), lipid peroxidation (LPO), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α) levels were measured. Caspase-3 activity was also assessed. Pre-incubation of hepatocytes with MEL (1 mM) and/or L-CAR (10 mM) 30 min prior to intoxication with MTX, significantly protected hepatocytes against toxicity. In addition, LPO, NO, TNF-α levels, and caspase-3 activity were decreased in comparison to the MTX-intoxicated group. Furthermore, the two drugs increased the MTX-depleted GSH level. MEL and L-CAR prevented MTX-induced hepatocytotoxicity, at least partly, by their antioxidative, antiinflammatory, and antiapoptotic effects. Further studies are recommended on the clinical pharmacologic and toxicologic effects of MEL and L-CAR in patients receiving MTX.
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- 2021
42. Quantitative detection of 6-thioguanine in body fluids based on a free-standing liquid membrane SERS substrate
- Author
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Zhe Feng, Zhengjun Gong, Jing Liu, Sha-Na Zhou, Wen Liu, Meikun Fan, Xin Zhao, and Dongmei Wang
- Subjects
Detection limit ,Antimetabolites, Antineoplastic ,Silver ,Materials science ,Chromatography ,Calibration curve ,Metal Nanoparticles ,Substrate (chemistry) ,Spectrum Analysis, Raman ,Biochemistry ,Analytical Chemistry ,symbols.namesake ,Membrane ,Limit of Detection ,symbols ,Humans ,Gold ,Thioguanine ,Spectroscopy ,Raman spectroscopy ,Suspension (vehicle) ,6-Thioguanine - Abstract
The adverse reactions caused by 6-thioguanine (6-TG) in anti-cancer treatment are closely related to the dose, leading to the urgent need for clinical monitoring of its concentration. In this work, a highly reproducible free-standing liquid membrane (FLM) surface-enhanced Raman spectroscopy (SERS) substrate was developed to detect 6-TG in human urine and serum quantitatively. Briefly, a prepared sample was adjusted to pH 2 and mixed with concentrated core–shell bimetallic nanoparticle (AgcoreAushell NP) suspension. The Au/Ag ratio of the AgcoreAushell NPs was optimized. Then the mixture was formed into an FLM using a custom mold. The relative standard deviation (RSD) of the experimental results can be stabilized below 10% (n ≥ 10). The R2 of the calibration curve in the range of 10 ~ 100 μg kg−1 was 0.988. In addition, the limit of detection (LOD) (3σ/k) of 6-TG was 5 μg kg−1. The FLM SERS platform has been successfully applied to the rapid and reliable analysis of 6-TG spiked in body fluids.
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- 2021
43. The Effects of Phyllanthus niruri Linn on Infiltrating Dendritic Cell and Ratio of Neutrophile/Lymphocytes in Chemotherapy of Sprague-Dawley Rats with Colorectal Cancer
- Author
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Michael Tendean and Ignatius Riwanto
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Male ,Antimetabolites, Antineoplastic ,Phyllanthus ,Neutrophils ,Colorectal cancer ,medicine.medical_treatment ,Lymphocyte ,Pharmacology ,Rats, Sprague-Dawley ,Lesion ,Capecitabine ,Leukocyte Count ,Immune system ,medicine ,Animals ,Lymphocytes ,Chemotherapy ,biology ,business.industry ,Dendritic Cells ,General Medicine ,Dendritic cell ,medicine.disease ,biology.organism_classification ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,medicine.symptom ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Background: Chemotherapy as part of colorectal cancer management can cause death to immunologically active tumor cell, but also it has immune suppressive effect. Phyllanthus niruri Linn is known to has immunomodulatory effect. This study was intended to prove P. niruri Linn effect on infiltrating dendritic cells and Neutrophil/lymphocyte ratios (NLRs) in Sprague–Dawley rats with colorectal cancer which were given capecitabine chemotherapy. Methods: The study was randomized post–test only control group design. The samples were 39 Sprague–Dawley male rats, with body weight around 170–220 grams, induced by 1,2-dimetylhydrazine (DMH) 30 mg/kgBW once per week subcutaneously. On 9th,11th and 13th week, there were four induced rats sacrificed each week to detect colorectal cancer (CRC) development. On the 13th week, all of the 4 sacrificed rats developed colon cancer, so the induction had to be stopped. The rest of 27 induced rats were randomly divided into three groups: control-group (K) were left untreated (9 rats), group P1 (9 rats) were given Capecitabine and group P2 (9 rats) were given Capecitabine with combination of P. niruri Linn extract 13.5 mg/kgBW orally. After 17th week, all rats were terminated and tumor lesion of colon were processed to be paraffin blocks and were stained with HE for evaluating the NLRs, and immunohistochemistry (S100) for evaluating infiltrating dendritic cells. Data was analyzed by using Oneway-Anova-test and post-Hoc LSD-test. Considered significant if p was
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- 2021
44. Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy
- Author
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Xiaoqiang Hu, Xiaopeng Wang, Wei Chen, Tao Chen, Sunwang Xu, Ruirong Lin, Cen Jiang, and Xiangjin Chen
- Subjects
Epigenomics ,Male ,Antimetabolites, Antineoplastic ,Cancer Research ,PAX5 Transcription Factor ,Elongator complex ,Mice, Nude ,Decitabine ,Deoxycytidine ,DNA methyltransferase ,Mice ,chemistry.chemical_compound ,Transcription (biology) ,Animals ,Humans ,Epigenetics ,RC254-282 ,DNA methylation ,Chemistry ,Research ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Gallbladder cancer ,Gemcitabine ,Chromatin ,Demethylating agent ,Oncology ,CpG site ,Cancer research ,Gallbladder Neoplasms - Abstract
Background Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown. Methods RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5. Results We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex. Conclusions Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.
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- 2021
45. Combination of azacytidine and curcumin is a potential alternative in decitabine-resistant colorectal cancer cells with attenuated deoxycytidine kinase
- Author
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Seigo Iwakawa, Ken-ichi Ogawara, Risako Seiki, and Mika Hosokawa
- Subjects
Antimetabolites, Antineoplastic ,Curcumin ,Methyltransferase ,Biophysics ,Decitabine ,Biochemistry ,chemistry.chemical_compound ,Cell Line, Tumor ,Cytidine Deaminase ,Antineoplastic Combined Chemotherapy Protocols ,Deoxycytidine Kinase ,medicine ,Humans ,Molecular Biology ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Drug Synergism ,Cell Biology ,Deoxycytidine kinase ,Cytidine deaminase ,Transfection ,DNA Methylation ,digestive system diseases ,DNA demethylation ,Drug Resistance, Neoplasm ,Cancer cell ,Azacitidine ,Cancer research ,Colorectal Neoplasms ,medicine.drug - Abstract
Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor is a novel anti-cancer drug regulating epigenetic mechanisms. Similar to conventional anti-cancer drugs, drug resistance to DAC also has been reported, resulting in tumor recurrence. Our previous study using colorectal cancer HCT116 cells found the decrease in deoxycytidine kinase (dCK) (activation enzyme of DAC) and the increase in cytidine deaminase (inactivation enzyme of DAC) in acquired DAC-resistant HCT116 (HCT116/DAC) cells. The aim of our study was to clarify the involvement of dCK and CDA in DAC resistance. In order to tackle DAC resistance, it was also examined whether other DNMT inhibitors such as azacytidine (AC) and polyphenols are effective in DAC-resistant cancer cells. When dCK siRNA was transfected into HCT116 cells, IC50 value of DAC increased by about 74-fold and reached that of HCT116/DAC cells with attenuated dCK. dCK siRNA to HCT116 cells also abolished DNA demethylation effects of DAC. In contrast, CDA siRNA to HCT116 cells did not influence the efficacy of DAC. In addition, CDA siRNA to HCT116/DAC cells with increased CDA did not restore the compromised effects of DAC. These results suggested that attenuated dCK but not increased CDA mainly contributed to DAC resistance. Regarding dCK in HCT116/DAC cells, a point mutation with amino acid substitution was observed while the product size and expression of mRNA coding region did not change, suggesting that dCK protein was decreased by post-transcriptional regulation. AC and polyphenols showed no cross-resistance in HCT116/DAC cells. AC but not polyphenols exerted DNA demethylation effect. Among polyphenols, curcumin (Cur) showed the most synergistic cytotoxicity in combination with AC while DNA demethylation effect of AC was partly maintained. Taken together, combination of AC and Cur would be a promising alternative to tackle DAC resistance mainly due to attenuated dCK.
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- 2021
46. Does dihydropyrimidine dehydrogenase level modify plasma antioxidant capacity in colorectal cancer patients treated with fluoropyrimidines?
- Author
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Marin P. Angelov, Velko Minchev, Kalina Kamenova, Liliya A. Atanasova, Slavina Surcheva, Nadya Hristova-Avakumova, Rumen Nikolov, and Lozan Todorov
- Subjects
Antimetabolites, Antineoplastic ,ABTS ,Colorectal cancer ,business.industry ,dihydropyrimidine dehydro ,colorectal cancer ,General Medicine ,Pharmacology ,medicine.disease ,Antioxidants ,Antioxidant capacity ,chemistry.chemical_compound ,chemistry ,medicine ,Dihydropyrimidine dehydrogenase ,Humans ,Medicine ,Fluorouracil ,Colorectal Neoplasms ,business ,Dihydrouracil Dehydrogenase (NADP) - Abstract
Introduction: Colorectal cancer is the third most common cancer type worldwide. Fluoropyrimidines and their prodrug-based regimens are widely applied as primary medications. The main enzyme responsible for the rate-limiting step in pyrimidine and for the 5-fluorouracil catabolism is dihydropyrimidine dehydrogenase (DPD). Aim: We aimed to screen DPD level and the changes of plasma antioxidant capacity of colorectal cancer patients on 5-fluorouracil regimen. Materials and methods: Human DPD Elisa Kit based on sandwich enzyme-linked immune-sorbent assay and spectrophotometric methods (FRAP and ABTS) were used in the study. Results: No statistically significant changes in plasma scavenging activity according to the results obtained in the ABTS system have been observed after evaluating all patients and considering DPD concentration. A decrease of the ferric reducing ability of patients’ plasma taken after the administered treatment was found. The increase of DPD level is accompanied by a decrease in the p values and therefore the statistical significance of the differences increases. Conclusions: Based on the aforementioned observations, it could be concluded that some aspects of plasma antioxidant capacity and individuals’ antioxidant status might be involved in the pathogenesis of the disease and could be altered by the activity of some enzymes. The cancer therapy in question, by the specificity of its mechanism of action, can modify patient’s oxidative status.
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- 2021
47. Efficacy and Safety of Additional S-1 Chemotherapy to S-1 Plus Oxaliplatin Regimen Chemotherapy for Stage III Gastric Carcinoma after Radical Resection
- Author
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Cheng Chen, Chun Lei Shen, San Xiong Huang, and Cheng Wu Tang
- Subjects
Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Gastroenterology ,Stomach Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Stage (cooking) ,Adverse effect ,Neoplasm Staging ,Retrospective Studies ,Tegafur ,Chemotherapy ,business.industry ,Hazard ratio ,Retrospective cohort study ,General Medicine ,Middle Aged ,Progression-Free Survival ,Oxaliplatin ,Drug Combinations ,Oxonic Acid ,Regimen ,Oncology ,Female ,business ,medicine.drug - Abstract
OBJECTIVE To investigate the efficacy and safety of additional S-1 chemotherapy to S-1 plus oxaliplatin (SOX) regimen chemotherapy for Stage III gastric carcinoma (GC) after radical resection. PATIENTS AND METHODS A total of 161 patients who were pathologically diagnosed as Stage III GC after D2 gastrectomy and received SOX regimen adjuvant chemotherapy between January 2012 and April 2016 were included in this retrospective study. SOX regimen postoperative chemotherapy was composed of Oxaliplatin and S-1, administrated every 3 weeks for 8 scheduled courses. After SOX chemotherapy, 76 patients preferred additional chemotherapy with S-1 (the ACT group), while additional S-1 chemotherapy was not given to the other 85 patients (control group). The ACT with S-1 was administrated every 3 weeks for 8 scheduled courses. Treatment was terminated in case of life-threatening adverse events or tumor progression, or patients' demand for termination. Progression-free survival (PFS), overall survival (OS), and adverse events were analyzed. RESULTS ACT group obtained markedly improved 3-year PFS [p = 0.04; hazard ratio (HR) for disease progression, 0.58; 95% confidence interval (CI), 0.34-0.98] and OS than the control group (p = 0.0469; HR for death, 0.56; 95% CI, 0.32-0.99). No chemotherapy-related mortality occurred. Patients of the ACT group suffered more common and severer hand-foot syndrome (HFS) (p = 0.02). CONCLUSIONS Additional S-1 chemotherapy may be helpful for improving the disease progression and survival for patients with Stage III GC after radical resection with an acceptable safety profile.
- Published
- 2021
48. Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury
- Author
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Raphael Teipel, Susanne Quick, Stephan Richter, Holger Knoth, Theresa Kretschmann, Frank Kroschinsky, Christoph Röllig, Ekaterina Balaian, Nael Alakel, Martin Bornhäuser, Sandra Heuschkel, Malte von Bonin, and Simone von Bonin
- Subjects
Adult ,Male ,Drug ,Antimetabolites, Antineoplastic ,Cancer Research ,media_common.quotation_subject ,Pharmacology ,Toxicology ,Folinic acid ,chemistry.chemical_compound ,medicine ,Humans ,Pharmacology (medical) ,In patient ,Adverse effect ,Aged ,media_common ,Creatinine ,Glucarpidase ,business.industry ,Acute kidney injury ,gamma-Glutamyl Hydrolase ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Methotrexate plasma concentration ,Recombinant Proteins ,Methotrexate ,High-dose methotrexate ,Oncology ,chemistry ,Half-dose glucarpidase ,Female ,Original Article ,business ,medicine.drug - Abstract
Purpose High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels. Methods Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17–32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography–mass spectrometry (LC–MS). Toxicities were assessed according to National Cancer Institute—Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80–455%) and showed toxic MTX plasma concentrations (range 3.1–182.4 µmol/L) before glucarpidase injection. The drug was administered 42–70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02–2.03 µmol/L. MTX rebound was detected in plasma 42–73 h after glucarpidase initiation, but concentrations remained consistent at Conclusion Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.
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- 2021
49. Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea
- Author
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Jung Woo Han, Jae Wook Lee, Hong Hoe Koo, Hana Cho, Che Ry Hong, Hyery Kim, Kyung-Nam Koh, Pil Sang Jang, Nack-Gyun Chung, Hoon Kook, Hee Young Shin, Bin Cho, Eu Jeen Yang, In Sang Jeon, Ho Joon Im, Keon Hee Yoo, Kyung Taek Hong, Chuhl Joo Lyu, Jung Yoon Choi, Young Tak Lim, Jong Jin Seo, Hyoung Jin Kang, Seongkoo Kim, and Seung Min Hahn
- Subjects
Adult ,Male ,0301 basic medicine ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Combination therapy ,Pediatric Cancer ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Acute lymphoblastic leukemia ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Republic of Korea ,medicine ,Humans ,Clofarabine ,Prospective Studies ,Child ,Adverse effect ,Childhood Acute Lymphoblastic Leukemia ,Salvage Therapy ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Combined Modality Therapy ,Pediatric cancer ,Pediatric malignancy ,Survival Rate ,Regimen ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Original Article ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,medicine.drug - Abstract
Purpose Effectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development.Materials and Methods In this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed up every 4-6 weeks for 6 months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed.Results Sixty patients (2-26 years old; 65% B-cell ALL, received prior ≥ 2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed 6 months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI], 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and one (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI, 4.7 to 6.1). Median duration of remission was 16.6 weeks (range, 2.0 to 167.6 weeks). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events.Conclusion Remission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.
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- 2021
50. RING-finger protein 6 promotes colorectal tumorigenesis by transcriptionally activating SF3B2
- Author
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Yunfei Zhou, Lei Liu, Weilin Li, Hui Xu, Jun Yu, Yan Li, Lifu Wang, and Chi Chun Wong
- Subjects
Male ,Antimetabolites, Antineoplastic ,Cancer Research ,Carcinogenesis ,Transgene ,Mice, Nude ,Apoptosis ,Biology ,Article ,Mice ,Gastrointestinal cancer ,Downregulation and upregulation ,In vivo ,Splicing factor 3b subunit 2 ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Genetics ,Organoid ,Animals ,Humans ,Chemotherapy ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,Cell growth ,Oncogenes ,Prognosis ,Xenograft Model Antitumor Assays ,In vitro ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Case-Control Studies ,Cancer research ,Epoxy Compounds ,Drug Therapy, Combination ,Fluorouracil ,Macrolides ,RNA Splicing Factors ,Colorectal Neoplasms ,Chromatin immunoprecipitation - Abstract
RNF6 is a RING finger protein with oncogenic potential. In this study, we established colon-specific RNF6 transgenic (tg) mice, and demonstrated that RNF6 overexpression accelerated colorectal carcinogenesis compared to wild-type littermates in a chemically induced colorectal cancer (CRC) model. To understand whether transcriptional activity of RNF6 underlies its oncogenic effect, we performed integrated chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis to identify splicing factor 3b subunit 2 (SF3B2) as a potential downstream target of RNF6. RNF6 binds to the SF3B2 promoter and the overexpression of RNF6 activates SF3B2 expression in CRC cells, primary CRC organoids, and RNF6 tg mice. SF3B2 knockout abrogated the tumor promoting effect of RNF6 overexpression, whereas the reexpression of SF3B2 recused cell growth and migration/invasion in RNF6 knockout cells, indicating that SF3B2 is a functional downstream target of RNF6 in CRC. Targeting of RNF6-SF3B2 axis with SF3B2 inhibitor with pladienolide B suppressed the growth of CRC cells with RNF6 overexpression in vitro and in vivo. Moreover, the combination of 5-fluorouracil (5-FU) plus pladienolide B exerted synergistic effects in CRC with high RNF6 expression, leading to tumor regression in xenograft models. These findings indicate that tumor promoting effect of RNF6 is achieved mainly via transcriptional upregulation of SF3B2, and that RNF6-SF3B2 axis is a promising target for CRC therapy.
- Published
- 2021
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