舟山群岛结直肠癌患者UGT1A1基因多态性与伊立替康临床疗效之间的相关性

Study on the correlation between UGT1A1 gene polymorphisms and irinotecan toxicity and efficacy in patients with colorectal cancer in Zhoushan archipelago

目的探讨舟山群岛结直肠癌患者中尿苷二磷酸葡糖醛酸转移酶1A1（UGT1A1）基因多态性与伊立替康（CPT-11）疗效和不良反应之间的相关性。方法以CPT-11为主的FOLFIRI方案治疗并随访,同时抽提外周血基因组DNA测定UGT1A1启动子区28（UUGT1A1＊28）的基因型,分析UGT1A1基因多态性及其与化疗毒性、疗效和预后之间的相关性。结果在78例使用CPT-11治疗的结直肠癌患者中,UGT1A1＊28野生型TA（6/6）有58例,占74.4%;杂合突变型TA（6/7）有16例,占20.5%;纯合突变型TA（7/7）有4例,占5.1%。UGT1A1＊28非野生型（6/7＋7/7）患者发生腹泻的概率明显高于野生型患者（χ^2=18.347,P=0.000）,而呕吐、中性粒细胞减少,以及疗效和存活状态与UGT1A1＊28基因多态性无关。UGT1A1＊28非野生型患者（6/7＋7/7）随着用药次数增加,腹泻（F=8.506,P=0.009）和中性粒细胞减少（F=5.262,P=0.034）等不良反应的发生率明显增大。UGT1A1＊28基因多态性不是独立的预后因素。结论舟山群岛UGT1A1＊28基因突变情况符合亚洲人的特征,以CPT-11为主的FOLFIRI方案治疗结直肠癌的疗效值得肯定,但需注意根据UGT1A1的基因型进行剂量调整。

AIM To analyze the distribution of UDP-glucuronosyhransferasel A1 （ UGT1 A 1 ）gene polymorphisms in patients with colorectal cancer（CRC） in Zhoushan archipelago, and evaluate correlations between UGTIA 1 gene poly- morphisms and irinotecan（CPT-11 ） , and the adverse reactions and efficacy of the drug in these patients. METHODS Patients with CRC were treated with FOLFIRI regimen（CPT-11 180 mg·m-2,iv gtt; LV 200 mg·m-2,iv gtt; 5-FU 400 mg·m-2, iv gtt）. UGT1A 1 ＊ 28 genotypes were determined by direct sequencing. Effect of UGT1A 1 gene polymorphisms on toxicity, efficacy and survival of chemotherapy were analyzed. RESULTS A total of 78 patients were collected to de- tect UGT1A1 gene polymorphisms. The rates of wild type（6/6）,heterozygous mutation（6/7） and homozygous mutation （7/7） of UGT1 A 1 ＊ 28 gene were 74.4 % （58/78）, 20.5 % （16/78） and 5.1% （4/78）, respectively. Ahhrough the in- cidence of diarrhoea in patients with UGT1A1 gene mutation was significantly higher than that with wild gene（ χ2 = 18. 347, P = 0.000）, but vomiting, neutropenia, efficacy and survival had no difference. With the increase of CPT-11 treatment course times, the incidence of diarrhea（ F = 8. 506, P = 0.009）, neutropenia（ F = 5.262, P = 0.034） be- came higher. UGT1A 1 gene polymorphisms were not enough to become a prognostic factors. CONCLUSION The distri- bution of UGT1A 1 gene polymorphisms accords with the characteristics of Asian people. The FOLFIRI regimen has a good effect on patients with CRC, but need to regulate the dosage corresponding to UGT1A 1 ＊ 28 genotypes.