Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity
Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity
复制标题
不同 UGT1A1 多态性与伊立替康诱导毒性的相关性
作者：
E. Rouits;M. Boisdron;A. Dumont;O. Guerin;A. Morel;E. Gamelin
目的：我们想评估尿苷二磷酸葡萄糖醛酸转移酶1A1 （UGT 1A1）基因的多态性：TATA盒多态性和UGT 1A1 G71R和Y486D编码序列突变，这是吉尔伯特综合征的主要突变，作为伊立替康（CPT-11）给药后严重毒性事件发生的预测因子。因此，我们在常规实践中建立了一种快速、灵敏、可靠的技术来检测CPT-11治疗前的高危患者。实验设计：75例接受CPT-11和5-氟尿嘧啶治疗的晚期结直肠癌患者进入研究。利用焦磷酸测序技术（实时测序）检测UGT 1A1编码区的TATA盒多态性和突变。同时对患者进行生化和临床评价以及对治疗的耐受性评估。结果：在人群中未发现G71R和Y486D突变。野生型6/6、杂合型6/7和吉尔伯特综合征7/7的UGT 1A1 TATA box多态性频率分别为41.7%、47%和9%。随着TA重复次数的增加，治疗耐受性降低，7/7组中71%的患者出现3/4级毒性。结论：所建立的方法适用于伊立替康治疗前的常规UGT 1A1多态性检测。这有助于检测吉尔伯特综合征纯合子或杂合子患者是否存在CPT 11诱导的毒性风险，从而有助于个体化剂量，优化疗效，限制毒性。
Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert’s syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert’s syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity. Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert’s syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.
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影响因子：
5.1
作者：
Bancroft, JD;Kreamer, B;Gourley, GR
通讯作者：
Gourley, GR
DOI：
10.1073/pnas.95.14.8170
发表时间：
1998-07-07
影响因子：
11.1
作者：
Beutler, E;Gelbart, T;Demina, A
通讯作者：
Demina, A
影响因子：
45.3
作者：
Gupta, E;Mick, R;Ratain, MJ
通讯作者：
Ratain, MJ
影响因子：
15.9
作者：
Iyer, L;King, CD;Ratain, MJ
通讯作者：
Ratain, MJ