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目的:探讨环磷酰胺(CPA)相关代谢酶基因多态性在乳腺癌人群中的分布及其对近期化疗疗效和不良反应的影响。方法:选取与CPA体内活化相关的5个酶基因的7个功能性多态位点,利用连接依赖性SNP复合分析技术,对338例汉族女性乳腺癌患者血标本进行分型检测,观察其多态性分布,并对其中107例具有完整疗效评价资料并接受含CPA化疗方案(76例FAC,31例CMF)的患者开展基因多态与疗效和毒副反应关系的分析。结果:CYP2B6*9和*4、CYP2C19*3、CYP2C9*3、CYP3A4*18、CYP3A5*3和*1D在338例乳腺癌人群中的变异频率分别为15.7%、23.0%、5.1%、3.7%、1.5%、70.7%和0.5%,单倍体CYP2B6*6变异频率为15.0%。在107例被评价患者中,各基因多态均未显示与临床疗效间差异有统计学意义的关联,P>0.05;进一步按FAC或CMF方案进行分组分析,也未发现这种关联,P>0.05。在107例患者中,与野生型CYP2B6*1/*1相比,CYP2B6*6携带者有更高的总不良反应发生率(20.7%vs41.5%,P=0.024),其风险被提高了3.13倍;按化疗方案分组后发现,该关联主要存在于FAC患者组(21.1%vs62.3%;P=0.009,OR=6.75)。结论:本研究所涉及的代谢酶基因多态在个体对CPA化疗敏感性上可能无重要作用,而在毒性耐受性上CYP2B6*6对FAC方案可能有预测价值,是否与不同药物之间的相互影响有关需要进一步研究。
Objective: To investigate the distribution of cyclophosphamide (CPA) -associated metabolic enzyme gene polymorphism in breast cancer patients and its effect on the efficacy and side effects of recent chemotherapy. Methods: Seven functional polymorphic loci of five enzyme genes related to activation of CPA in vivo were selected and 338 cases of Han women with breast cancer were genotyped by using connection-dependent SNP analysis. We also analyzed the relationship between gene polymorphism, efficacy and adverse reactions in 107 patients with complete response data and receiving CPA chemotherapy regimens (76 FACs and 31 CMFs). Results: The frequency of variation of CYP2B6 * 9 and * 4, CYP2C19 * 3, CYP2C9 * 3, CYP3A4 * 18, CYP3A5 * 3 and * 1D in 338 breast cancer patients were 15.7%, 23.0%, 5.1% and 3.7% , 1.5%, 70.7% and 0.5%, respectively. The haplotype CYP2B6 * 6 frequency was 15.0%. In the 107 patients evaluated, there was no significant correlation between the polymorphisms and the clinical efficacy, P> 0.05; further analysis by FAC or CMF group did not find this association, P> 0.05. CYP2B6 * 6 carriers had a higher overall adverse event rate (20.7% vs 41.5%, P = 0.024) in 107 patients compared to wild-type CYP2B6 * 1 / * 1, with an increased risk 3.13 times. According to the chemotherapy regimen, the association was mainly found in the FAC group (21.1% vs62.3%; P = 0.009, OR = 6.75). CONCLUSION: The polymorphisms of metabolic enzyme genes involved in this study may not play an important role in the individual sensitivity to chemotherapy with CPA. CYP2B6 * 6 may have predictive value for FAC regimen in toxicity tolerance and whether it is compatible with different drugs Interactions need further study.