Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka City, Shizuoka, Japan.
Tohoku J Exp Med. 2013 Feb;229(2):107-14. doi: 10.1620/tjem.229.107.
A prodrug, irinotecan (CPT-11), is a semisynthetic derivative of camptothecin. It inhibits topoisomerase I and is used for treatment of lung, stomach, and colon cancers in Japan. The active form of CPT-11, SN-38, causes the adverse events such as neutropenia and diarrhea. Since SN-38 is metabolized to non-toxic SN-38-glucuronide by hepatic uridine diphosphate glucuronosyl transferase (UGT) 1A enzymes, UGT1A enzyme activities may influence adverse events of CPT-11. UGT1A enzymes consist of three isozymes (1A1, 1A7, 1A9), and their genes are characterized by polymorphisms. Here, to identify the genetic factors that affect the adverse events of CPT-11, we determined the polymorphism in three UGT 1A isozyme genes in 45 inpatients with lung, colon, or stomach cancer. The univariate and multivariate analysis of patients' physiological and genetic factors revealed that one or more genotypes of UGT1A16/28, UGT1A73/3, and UGT1A91/1 may enhance the adverse events. Each of the first two genotypes is expected to generate the enzyme with low catalytic activity. The UGT1A91 represents the wild-type allele, which however provides the lower catalytic activity, compared to the UGT1A922 variant that is common in this study population. Indeed, four (67%) out of six patients who carry one or more of the above-mentioned genotypes suffered from adverse events, leading to the discontinuation of chemotherapy or the decreased dose of CPT-11. By contrast, only six (15%) out of 39 patients with other genotypes suffered from adverse events. In conclusion, UGT1A1*6/28, UGT1A73/3, and UGT1A91/*1 should be taken into consideration as markers for preventing severe adverse events of CPT-11 administration.
前药伊立替康（CPT-11）是喜树碱的半合成衍生物。它抑制拓扑异构酶 I，用于治疗日本的肺癌、胃癌和结肠癌。CPT-11 的活性形式 SN-38 会引起中性粒细胞减少和腹泻等不良反应。由于 SN-38 被肝 UDP 葡萄糖醛酸转移酶（UGT）1A 酶代谢为非毒性的 SN-38-葡萄糖醛酸苷，UGT1A 酶活性可能会影响 CPT-11 的不良反应。UGT1A 酶由三种同工酶（1A1、1A7、1A9）组成，其基因具有多态性。在这里，为了确定影响 CPT-11 不良反应的遗传因素，我们在 45 名肺癌、结肠癌或胃癌住院患者中确定了三个 UGT1A 同工酶基因的多态性。对患者生理和遗传因素的单因素和多因素分析表明，UGT1A16/28、UGT1A73/3 和 UGT1A91/1 的一种或多种基因型可能会增强不良反应。前两种基因型中的每一种都预计会产生催化活性低的酶。UGT1A91 代表野生型等位基因，但与本研究人群中常见的 UGT1A922 变体相比，其催化活性较低。事实上，携带上述一种或多种基因型的 6 名患者中有 4 名（67%）出现不良反应，导致化疗停止或 CPT-11 剂量减少。相比之下，在具有其他基因型的 39 名患者中只有 6 名（15%）出现不良反应。总之，UGT1A1*6/28、UGT1A73/3 和 UGT1A91/*1 应作为预防 CPT-11 给药严重不良反应的标志物加以考虑。
