ABSTRACT
OBJECTIVE: Our study aimed to investigate the association between cytochrome P450 1A1 (CYP1A1) polymorphisms (T3801C and A2455G) and acute lymphoblastic leukemia (ALL) risk, considering genetic models and ethnicity. MATERIALS AND METHODS: PubMed, Embase, Web of Knowledge, Scopus, and the Cochrane electronic databases were searched using combinations of keywords related to CYP1A1 polymorphisms and the risk of ALL. Studies retrieved from the database searches underwent screening based on strict inclusion and exclusion criteria. RESULTS: In total, 2822 cases and 4252 controls, as well as 1636 cases and 2674 controls of the C3801T and A2455G variants of CYP1A1, respectively, were included in this meta-analysis. The T3801C polymorphism of CYP1A1 significantly increases the risk of ALL, particularly those observed in Asian and Hispanic populations, independent of age. Similarly, the A2455G polymorphism of CYP1A1 plays a significant role in the susceptibility to ALL in all genetic models, except the heterozygous form. This association was observed mainly in mixed populations and in both children and adults (except in the heterozygous model). CONCLUSION: Our comprehensive analysis indicates that the T3801 and A2455G polymorphisms of CYP1A1 may increase the risk of ALL depending on ethnicity. Therefore, both variants should be considered promising biomarkers for ALL risk. Further large-scale investigations are necessary to assess other factors, such as gene-gene or gene-environment interactions.
ABSTRACT
INTRODUCTION: Imatinib is a first-line selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia. Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the mechanism of imatinib-induced hepatotoxicity has rarely been investigated. CASE REPORT: We report a 51-year-old man, suffering from acute toxic hepatitis after 5 months of imatinib treatment for chronic myeloid leukemia. MANAGEMENT AND OUTCOME: The outcome was favorable after discontinuation of treatment with normalization of biological liver function after 12 weeks. The treatment was switched to nilotinib without any incidents. DISCUSSION: Regular liver function test monitoring is recommended during imatinib treatment. In fact of acute hepatic toxicity, treatment with imatinib should be stopped in the case of cytolysis more than five times the upper limit of normal.
Subject(s)
Chemical and Drug Induced Liver Injury , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Male , Middle Aged , Antineoplastic Agents/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Imatinib Mesylate/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: The P-glycoprotein (P-gp) is one of the mechanisms of Imatinib (IM) resistance in chronic myeloid leukemia (CML). P-gp has been identified as an efflux pump involved in releasing of IM outside CML cells. To date, the P-gp involvement in the IM resistance development was not completely understood. Therefore, the present study aimed at measuring the P-gp expression level on lymphocytes from Tunisian patients with CML and correlating this level with a molecular response to IM. METHOD: The expression of P-gp on peripheral blood lymphocytes from 59 Tunisian patients with CML (27 IM responder patients vs 32 IM non-responder patients) was evaluated by flow cytometry. RESULT: Our finding showed significantly positive expression of P-gp in the lymphocytes from the IM non-responder group when compared to the IM-responder group (P = .001). In IM non-responder CML patients, the comparison between CCyR achievers and non-achievers showed a high mean fluorescence intensity (MFI) of P-gp expression in patients who did not achieve their CCyR (P = .001). The comparison between patients with primary and secondary resistance to IM showed an increasing MFI value in patients with primary resistance to IM (P = .001). Besides, the comparison between nilotinib-treated and dasatinib-treated patients proved a high value of MFI in nilotinib-treated patients (P = .001). CONCLUSION: The overexpression of P-gp on lymphocytes has significantly correlated with the failed molecular response to IM in patients with CML.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/metabolism , Drug Resistance, Neoplasm , Imatinib Mesylate/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Case-Control Studies , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Prognosis , Retrospective Studies , Survival RateABSTRACT
CONTEXT: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, mainly the C677T, have been implicated as risk factors for several cancers as the acute lymphoblastic leukemia (ALL). In addition, a potential effect of such variant on the efficacy of methotrexate (MTX) has been reported. OBJECTIVE: In this study, we evaluated the impact of the C677T variant of MTHFR on MTX-related toxicity in ALL patients from Tunisia; to provide new insights for a personalized therapy based on the human genotype. MATERIALS AND METHODS: Genotyping was carried out with restriction fragment length polymorphism (RFLP) on blood samples from a total of 35 younger patients; suffering from ALL. RESULTS: In the ALL patients, the MTHFR 677CT genotype confers a greater risk of toxicity with 1.3 times as relative risk mainly the hepatic toxicity when compared with MTHFR 677CC. CONCLUSION: Our findings suggest that C677T polymorphism of MTHFR seems to be a good marker for MTX-related toxicity in ALL.
