Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events in Cancer Patients Receiving Irinotecan-Based Chemotherapy

Abstract

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 UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 may enhance the adverse events. Each of the first two genotypes is expected to generate the enzyme with low catalytic activity. The UGT1A9*1 represents the wild-type allele, which however provides the lower catalytic activity, compared to the UGT1A9*22 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, UGT1A7*3/*3, and UGT1A9*1/*1 should be taken into consideration as markers for preventing severe adverse events of CPT-11 administration.