UGT1AI*6 and UGT1A1*27 for individualized irinotecan chemotherapy

Genetic polymorphisms of uridine 5'-diphospho-glucuronosyl-transferase (UGT)1A1, a crucial drug-metabolizing enzyme of the anticancer drug irinotecan, are essential determinants of individual variation in susceptibility to irinotecan-related toxicity. The FDA has revised the package insert of irinotecan in order to warn of the association between toxicity and UGTIA1*28, a variant sequence in a promoter region of the UGTIA1 gene. Unlike UGT1A1*28, UGT1AI*6 and UGTIA1*27 polymorphisms are found in a coding region of the gene, and are known to directly reduce the activity of the UGT enzyme. Therefore, it is reasonable to assume that the presence of UGT1A1*6 or UGTIA1*27 would also increase the risk of irinotecan toxicity. Importantly, UGTIA1*6 and UGT1Al*27 have only been identified in the Asian population. Although conclusive evidence linking UGTIAI*6 and/or UGT1Al*27 to irinotecan toxicity is insufficient at this time, these variants should be tested in addition to UGTIA1*28 for more individualized irinotecan chemotherapy, especially among the Asian population.