壮族人群UGT1A1基因多态性与伊立替康治疗结直肠癌个体反应差异相关性的实验研究

Pharmacogenomics and the efficacy 、toxicity-related marks of specific chemotherapy drugs is the research focus of individual therapy ．The primary drug resistance and the acquired drug resistance is common for metastatic colorectal cancer. Irinotecan is activated by carboxylesterases to SN38 in human body, which shows antitumor activity by inhibiting topoisomerase 1 (Topo 1). SN38 is mainly glucuronidated by uridine diphosphate glucuronosyltransferases 1A1 (UGT1A1) to form the inactive metabolite SN38 glucuronide (SN38G). Patients with a UGT1A1*28 or UGT1A1*6 mutation are less capable to metabolize SN38 to SN38-G, thus need to reduce the amount of irinotecan to avoid leucopenia and/or diarrhea, compared to the wild-type patients.However, no precise genotype-dosage relationship has been advised yet. For the ethnic and genetic background of diet in different living environment, Zhuang chinese patients with colorectal cancer receive irinotecan therapy should not completely copy Europe and the United States or Chinese Han patients scheme. We aim to investigate the optimal dosage of irinotecan in the FOLFIRI protocol for the Zhuang Chinese patients with metastatic colorectal cancer in Guangxi province based on their UGT1A1*28 and *6 genotype and evaluate if Topo 1 immunohistochemistry is an effective biomarker for irinotecan application。We will construct a nude mouse model bearing human colorectal tumors, and explore the optimal protocol to prevent irinotecan induced delayed diarrhea with this model. Briefly,we aim to achieve the goal of individual therapy of irinotecan in three aspects, namely to investigate a biomarker for irinotecan indication, to personalized dosage of irinotecan according to different UGT1A1 genotypes and to explore the optimal protocol for preventing irinotecan induced delayed diarrhea.

药物遗传基因组学、特殊化疗药物疗效及毒性反应相关标志物是个体化治疗领域的研究热点。结直肠癌化疗中原发性与获得性耐药的现象很普遍。伊立替康在体内转化为活性成分SN38后主要经UGT1A1解毒成SN38G排出体外。Topo 1是SN38的分子靶点。伊立替康UGT1A1发生*28或*6突变后功能下降，需减少伊立替康剂量以避免ADR。由于各民族遗传背景和饮食生活环境不同，壮族结直肠癌患者接受伊立替康治疗时不应当完全照搬欧美或者中国汉族患者的方案。本课题主要探讨广西壮族人群UGT1A1基因多态性与伊立替康治疗结直肠癌个体反应差异的相关性，并利用免疫组化技术，探讨肿瘤组织Topo1蛋白表达高低可否作为伊立替康用药的生物标记物，同时构建裸鼠荷瘤模型，探讨伊立替康致迟发性腹泻的防治机制，并将在临床患者中验证该方案。结合此三方面作用机制展开研究，从而真正实现个体化治疗的目的。

伊立替康为主的方案是转移性结直肠癌患者的主要化疗方案，由于各民族遗传背景和饮食生活环境不同，壮族转移性结直肠癌患者接受伊立替康化疗时不应当完全照搬欧美或者中国汉族患者的方案。伊立替康在体内转化为活性成分SN38后主要经UGT1A1解毒成SN38G排出体外，Topo 1是SN38的分子靶点,伊立替康UGT1A1发生*28或*6突变后功能下降，需减少伊立替康剂量以避免药物不良反应。本课题的研究内容主要是探讨广西壮族人群UGT1A1基因多态性与伊立替康治疗结直肠癌个体反应差异的相关性，并利用免疫组化技术，探讨肿瘤组织Topo1蛋白表达高低可否作为伊立替康用药的生物标记物，同时构建裸鼠荷瘤模型，探讨伊立替康致迟发性腹泻的防治机制，并将在临床患者中验证该方案。结合此三方面作用机制展开研究，从而实现个体化治疗的目的.通过研究，我们发现入组的广西壮族患者UGT1A1基因多态性的分布提示UGT1A1*28杂合突变型（TA6/7）占30.2%,无纯合突变型（TA7/7）, UGT1A1*6 杂合突变型（G/A）占20.9%，纯合突变型（A/A）占2.3%；广西壮族患者UGT1A1基因多态性对伊立替康化疗相关的腹泻及中性粒细胞减少的发生各有相关性并依据其剂量调整；UGT1A1基因多态性与伊立替康化疗的疗效无明显相关性； TOPO-1 的表达情况与其临床病理特征无明显相关性；TOPO-1表达可能可以预测转移性结直肠癌伊立替康化疗敏感性，可能可以作为转移性结直肠癌伊立替康化疗近期疗效的预测因子。TOPO-1高表达均较低表达病人存在更长的无进展生存（PFS），其表达情况可能可以作为判断转移性结直肠癌预后的一项指标。我们通过构建裸鼠荷瘤模型，探讨伊立替康致迟发性腹泻的防治机制，初步筛选出黄芩苷在预防伊立替康所致的腹泻上较其它药物似乎有较好疗效的趋势，并将在临床患者中验证该方案.药物遗传基因组学、化疗药物疗效及毒性反应相关预测因子是个体化治疗领域的研究热点和发展趋势，随着精准医疗时代其技术的成熟和不断发展，有望最终完全实现量体裁衣的个体化治疗目的。