RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia
| العنوان: | RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia |
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| المؤلفون: | Alok Srivastava, Kavitha M Lakshmi, Sreeja Karathedath, Wei Zhang, Ashok Kumar Jayavelu, Aby Abraham, Ramachandran V Shaji, Vivi M. Srivastava, Poonkuzhali Balasubramanian, Nancy Beryl Janet, Auro Viswabandya, Chepsy C Philip, Ajay Abraham, Savitha Varatharajan, Biju George, Vikram Mathews, Mammen Chandy, Ezhilpavai Mohanan |
| المصدر: | Pharmacogenomics |
| بيانات النشر: | Future Medicine Ltd, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Adult, Male, Antimetabolites, Antineoplastic, Adolescent, Ribonucleoside Diphosphate Reductase, Daunorubicin, Apoptosis, Pharmacology, Biology, Article, Disease-Free Survival, Equilibrative Nucleoside Transporter 1, Cytidine Deaminase, Deoxycytidine Kinase, Gene expression, Genetics, medicine, Humans, MTT assay, Aged, Gene Expression Regulation, Leukemic, Tumor Suppressor Proteins, Cytarabine, Myeloid leukemia, Deoxycytidine kinase, Middle Aged, carbohydrates (lipids), Gene expression profiling, Leukemia, Myeloid, Acute, Drug Resistance, Neoplasm, Cancer research, Molecular Medicine, Female, Ex vivo, medicine.drug |
| الوصف: | 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 |
| تدمد: | 1744-8042 1462-2416 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b5ab16a210a0a448df1ce23bfb6fb910Test https://doi.org/10.2217/pgs.15.44Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b5ab16a210a0a448df1ce23bfb6fb910 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17448042 14622416 |
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