Study Of The Association Between Single Nucleotide Polymorphisms Of Drug Metabolism And Transport Related Genes And The Outcomes Of Anti-tumor Drugs

Background:Effect of antitumor drugs is greatly different between individuals. Phamacogenomics aims to identify the inherited basis for interindividual difference in drug response, and translate this to molecular diagnostics that can be used to individualize drug therapy.Methods:We select the peripheral blood sample of advanced non-small cell lung cancer patients who administered docetaxel or vinorelbine. PCR-RFLP method was used in this research to detect SNPs. We chose 4 SNPs, 1 of CYP3A5, 2 of drug transportor MDR1 and 1 of Cyclooxygenase-2 which was reported to regulate the expression of MDR1. Chi-square test was used to analyze relationship between genotypes and clinical chemotherapy effects. To confirm our results, we analyzed the relationship beteen MDR1 mRNA/P-gp expression and MDR1 C3435T/G2677T(A) genotypes.Results:1. No significant difference was observed between the CYP3A5 genotypes and effects to docetaxel-platinum and vinorelbine-platinum.2. Patients with C/C homozygous at MDR1-3435 site were significantly more sensitive(response rate 60%) to vinorelbine-platinum than others(response rate 34%)(OR=1.76, P=0.033).3. Patients with C/C homozygous at MDR1-3435 site(response rate 50%) were a little more sensitive to docetaxel-platinum than C/T heterozygous and T/T homozygous(response rate 34%)( P=0.123).4. Patients with G/G wild homozygous in MDR1 2677 site have a significantly higher response rate of 61% to vinorelbine-platinum than others(response rate 30%) (P=0.012).5. Patients with G/G wild homozygous in MDR1 2677 site have a significantly higher response rate of 56% to docetaxle-platinum than others(response rate 28.6%) (P=0.035).6. Patients with A/A mutant homozygous in COX-2 G-1195A site have a little higher response rate of 36.7% to vinorelbine-platinum than others (response rate 36.7%) (P=0.067). The difference is not significant. The response rates to docetaxel-platinum were almost equal among patients with different genotypes at COX-2 G-1195A site (P>0.05) .7. Individuals having C/T or T/T at MDR1 3435 have more mRNA and P-gp expression than those having C/C wild homozygous(p=0.025).8. Individuals having G/G wild homozygous at MDR1 2677 site have a little higher mRNA and P-gp than others, but the difference is not significant (p>0.05) .Conclusion:1. Polymorphisms of CYP3A5—22893 and COX-2-1195 might not be associated with efficiency of patients with advanced NSCLC after treatment with vinorelbine-platinum/docetaxel-platinum chemotherapy;2. Polymorphisms of MDR1 C3435T might be associated with efficiency of patients with advanced NSCLC after treatment with vinorelbine-platinum chemotherapy which might be a prognostic factor in Vinorelbine-platinum treated patients with advanced NSCLC but might not be associated with efficiency in docetaxel-platinum treated ones;3. Polymorphisms of MDR1 2677 might be associated with efficiency of patients with advanced NSCLC after treatment with vinorelbine-platinum/docetaxel-platinum chemotherapy which might be a prognostic factor in Vinorelbin-platinum/docetaxel-platinum treated patients with advanced NSCLC;5. Polymorphisms of MDR1C3435T might be associated with expressionof ABCB1 mRNA or P-gp in lung tumor tissue but MDR1 G2677T(A)might not be so.