Dataset Information

Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers.

ABSTRACT: Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.

SUBMITTER: Di Francia R

PROVIDER: S-EPMC7956511 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers.

Di Francia Raffaele R Crisci Stefania S De Monaco Angela A Cafiero Concetta C Re Agnese A Iaccarino Giancarla G De Filippi Rosaria R Frigeri Ferdinando F Corazzelli Gaetano G Micera Alessandra A Pinto Antonio A

Cancers 20210225 5

Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the i ...[more]

PMID: 33669053

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Project description:BACKGROUND:Variation in terms of outcome and toxic side effects of treatment exists among acute myeloid leukemia (AML) patients on chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Candidate Ara-C metabolizing gene expression in primary AML cells is proposed to account for this variation. METHODS:Ex vivo Ara-C sensitivity was determined in primary AML samples using MTT assay. mRNA expression of candidate Ara-C metabolizing genes were evaluated by RQPCR analysis. Global gene expression profiling was carried out for identifying differentially expressed genes between exvivo Ara-C sensitive and resistant samples. RESULTS:Wide interindividual variations in ex vivo Ara-C cytotoxicity were observed among samples from patients with AML and were stratified into sensitive, intermediately sensitive and resistant, based on IC50 values obtained by MTT assay. RNA expression of deoxycytidine kinase (DCK), human equilibrative nucleoside transporter-1 (ENT1) and ribonucleotide reductase M1 (RRM1) were significantly higher and cytidine deaminase (CDA) was significantly lower in ex vivo Ara-C sensitive samples. Higher DCK and RRM1 expression in AML patient's blast correlated with better DFS. Ara-C resistance index (RI), a mathematically derived quotient was proposed based on candidate gene expression pattern. Ara-C ex vivo sensitive samples were found to have significantly lower RI compared with resistant as well as samples from patients presenting with relapse. Patients with low RI supposedly highly sensitive to Ara-C were found to have higher incidence of induction death (p = 0.002; RR: 4.35 [95% CI: 1.69-11.22]). Global gene expression profiling undertaken to find out additional contributors of Ara-C resistance identified many apoptosis as well as metabolic pathway genes to be differentially expressed between Ara-C resistant and sensitive samples. CONCLUSION:This study highlights the importance of evaluating expression of candidate Ara-C metabolizing genes in predicting ex vivo drug response as well as treatment outcome. RI could be a predictor of ex vivo Ara-C response irrespective of cytogenetic and molecular risk groups and a potential biomarker for AML treatment outcome and toxicity. Original submitted 22 December 2014; Revision submitted 9 April 2015.

Dataset Information

Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers.

Publications

Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers.

Similar Datasets

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