【作者】 潘继红；

【导师】 韩金祥；

【作者基本信息】 山东大学 ， 生物化学与分子生物学， 2007， 博士

【摘要】 背景：肿瘤的发生是一个十分复杂的生物学过程，是遗传因素和环境因素相互作用的结果。化疗是肿瘤治疗中非常重要的一种方法，临床上患者对化疗的反应具有很大的差异性，同样的化疗方案适用于一个人群可能不适用另一个人群。临床合理用药的核心是个体化给药。随着基因组作图的成功，许多基因的SNP被发现，人们越来越多地认识到用药个体化与基因多态性的关系，药物基因组学也就应运而生。研究方法：我们选择了临床上接受化疗的肿瘤患者的血标本进行人类药物代谢酶CYP3A5，药物转运蛋白MDR1和调节MDR1表达的COX-2共三个基因的四个SNP位点进行分型，共完成54例多西他赛和69例长春瑞滨化疗的非小细胞肺癌患者的分型，并结合临床疗效进行了统计分析。为了验证我们的结果，我们又分析了31例肺癌患者肺癌手术切除组织中MDR1 C3435T与G2677T(A)两位点与MDR1 mRNA和P-gp表达量之间的关系。结果：1．CYP3A5—22893位点各基因型有效率没有明显差异；2．长春瑞滨—铂类治疗的MDR1 C3435T位点C／C野生型纯合子个体有效率为60％(95％CI 0.408,0.792)，而杂合子(C／T)和突变型纯合子(T／T)个体有效率为34％(95％CI 0.2，0.48)。经统计分析前者明显高于后两者(OR=1.76，P=0.033)。3．多西他赛—铂类治疗的MDR1 C3435T位点各基因型之间虽然没有统计学差异，但野生型纯合子(C／C)个体有效率为50％，大于杂合子(C／T)和突变型纯合子(T／T)个体有效率31％(P=0.123)。4．长春瑞滨—铂类治疗的MDR1 G2677T(A)位点野生型纯合子(G／G)个体有效率为61％(95％CI 0.441，0.779)(19 response of 32 patients)，而其他基因型个体总有效率为30％(95％CI 0.462,0.758,11 response of 37 patients)。经统计分析前者明显高于后者。(OR=2.0，P=0.012)。5．多西他赛—铂类治疗的MDR1 G2677T(A)位点野生型纯合子(G／G)个体有效率为56％(11response of 19)，而其他基因型个体总有效率为28.6％(10 response of 35 patients)。经统计分析前者明显高于后者。(P=0.035)。6．长春瑞滨—铂类方案对COX-2-1195位点野生型纯合子G／G及杂合子G／A个体的有效率为36.7％(18 of 49 patients)，而突变型纯合子A／A个体的有效率为60％(12 of 20 patients)。后者有效率高于前者，但没有统计学差异(p=0.067)。多西他赛—铂类方案对COX-2 G-1195A各基因型个体有效率均相近，无统计学差异(P＞0.05)。7．MDR1 C3435T位点基因型与ABCB1 mRNA和P-gp表达有关，表达量趋势为C／C＜C／T+T／T。8．MDR1 G2677T(A)位点G／G基因型的ABCB1 mRNA和P-gp表达略高于其他基因型，但没有明显差异(p＞0.05)。结论：1．CYP3A5—22893位点和COX-2-1195位点各基因型与晚期NSCLC患者长春瑞滨—铂类／多西他赛—铂类化疗疗效无关；2．MDR1基因C3435T位点基因型与晚期NSCLC患者长春瑞滨—铂类化疗疗效有关，在一定程度上可以判断晚期NSCLC患者长春瑞滨—铂类化疗预后；MDR1基因C3435T位点基因型与晚期NSCLC患者多西他赛—铂类化疗疗效无关；3．MDR1 G2677T(A)位点基因型与晚期NSCLC患者长春瑞滨—铂类／多西他赛—铂类化疗疗效有关，在一定程度上可以判断晚期NSCLC患者长春瑞滨—铂类化疗预后；4．C3435T位点基因型与ABCB1 mRNA和P-gp表达有关；G2677T(A)位点G／G基因型的ABCB1 mRNA和P-gp表达无关。更多还原

【Abstract】 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.更多还原