Meta-Analysis on Pharmacogenetics of Platinum-Based Chemotherapy in Non Small Cell Lung Cancer (NSCLC) Patients

AIM: To determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients. METHODS: Publications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI). RESULTS: Data were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11-3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44-4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17-0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. CONCLUSION: Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future

A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions

P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood–brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1GT1292-3TG (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1GT1292-3TG recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1GT1292-3TG recombinant cells exposed exhibited a 75% decrease in IC50 for doxorubicin (162.6 ± 17.4 to 37.9 ± 2.6 nM) and a 50% decrease in IC50 for paclitaxel (155.7 ± 27.5 to 87.7 ± 9.2 nM), vinblastine (128.0 ± 15.9 to 65.9 ± 5.1 nM), and vincristine (593.7 ± 61.8 to 307.3 ± 17.0 nM). The effects of the Cys431Leu variation, due to MDR1GT1292-3TG nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p < 0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p < 0.05). Collectively, these data suggest MDR1GT1292-3TG variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype