The role of UGT1A1*28 polymorphism in the pharmacodynarnics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer
The role of UGT1A1*28 polymorphism in the pharmacodynarnics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer
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DOI：
10.1200/jco.2005.05.5400
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发表时间：
2006-07-01
影响因子：
45.3
通讯作者：
Frustaci, Sergio
中科院分区：
文献类型：
--
作者：
Toffoli, Giuseppe;Cecchin, Erika;Frustaci, Sergio
目的UGT 1A 1 *28多态性与伊立替康活性代谢产物SN 38的葡萄糖醛酸化降低相关。这可能会增加毒性与此agent.Patients和MethodsIn一项前瞻性研究，250转移性结直肠癌患者。接受伊立替康、氟尿嘧啶和亚叶酸作为一线治疗。研究UGT 1A 1 *28多态性与血液学和非血液学毒性、客观缓解率和生存率的分布。在一个患者亚组中研究了药代动力学结果UGT 1A 1 *28基因多态性与3 ~ 4级血液学毒性的发生风险相关（优势比[OR]，8.63; 95% CI，1.31 - 56.55），仅与第一个周期相关，与野生型TA（6）/TA（6）相比，在整个治疗期间，对于具有两个变异等位基因TA（7）/TA（7）的患者没有观察到。TA（7）TA（7）患者的缓解率也高于TA（6）/TA（6）患者（OR，0.32; 95% CI，0.12 - 0.86）。与TA（6）/TA（6）患者相比，TA（7）/TA（7）患者的生存优势不显著（风险比，0.81; 95% CI，0.45 - 1.44）。较高的缓解率可通过不同的药代动力学和较高的胆汁指数[伊立替康曲线下面积（AUC）X（SN 38 AUC/SN 38 G AUC）]和较低的葡萄糖醛酸化率（SN 38 G AUC/SN 38 AUC）与TA（7）/TA（7）基因型和更高的反应率相关，结论UGT 1A 1 *28基因多态性与药物毒性有一定的相关性;然而，它的重要性没有以前较小的审判中所讨论的那么大。特别是，该分析结果不支持UGT 1A 1 *28多态性患者中伊立替康剂量降低的可能性。
PurposeUGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.Patients and MethodsIn a prospective study, 250 metastatic colorectal cancer patients.-were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic,and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.ResultsUGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA(7)/TA(7) compared with wild-type TA(6)/TA(6). The response rate was also higher in TA(7)TA(7) patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA(6)/TA(6). A nonsignificant survival advantage was observed for TA(7)/TA(7) when compared with TA(6)/TA(6) patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)X(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA(7)/TA(7) genotype and a higher response rate, indicating that the polymorphism is functionally relevant.ConclusionThe results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the,result of this analysis.