CYP3A4 and CYP3A5 Genes in Cyclophosphamide-treated Chronic Lymphocytic Leukemia Patients: A Pharmacogenetics Study

Résumé

Background: Approximately 75% of drug metabolism in clinical settings is attributed to cytochrome P450 enzymes. This study aimed to assess the effects of the CYP3A4*1B and CYP3A5*3 genetic variations on the clinical results of individuals with chronic lymphocytic leukemia (CLL) following cyclophosphamide treatment. Furthermore, we aimed to ascertain how well the inflammatory condition affects the therapeutic response. Methods: CYP3A4*1B and CYP3A5*3 polymorphisms were examined in 150 Egyptian CLL patients using allele-specific amplification (ASA)-polymerase chain reaction (PCR); serum interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were also measured to assess the non-genetic inflammatory effect on CYP3A4 and CYP3A5 genes. Patients further received chemotherapy and were subsequently followed up. Results: The allelic frequencies of the CYP3A4*1B gene were (74.3% A-allele vs. 25.7% G-allele), and for CYP3A5*3, these frequencies were (73.4% A-allele vs. 26.6% G-allele). Patients with the CYP3A4*1B and CYP3A5*3 genes, or both variants, were less likely to respond than the normal patients (p < 0.001). Regarding the non-genetic inflammatory effect, patients in the response group who achieved partial remission were characterized by higher IL-6 and TNF-α values than those who achieved complete remission (p < 0.001), and patients in the non-response group who had a progressive disease were characterized by higher IL-6 and TNF-α values than those who had a stable disease (p < 0.001). Conclusion: CYP3A4*1B and CYP3A5*3 variants could be helpful indicators in predicting the response to cyclophosphamide chemotherapy. CYP3A4 and CYP3A5 variability should be factored into personalized medicine, which attempts to optimize drug dosing for individual patients by considering genetic and non-genetic factors affecting the response.

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