UGT1A1 Promoter Genotyping

Irinotecan, also known as Camptosar® or CPT-11, is an anti-neoplastic agent used to treat colorectal cancers. Uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) is responsible for the metabolic inactivation of SN-38 (active form of Irinotecan) via glucuronidation. Individuals with low levels of UGT1A1 activity are at increased risk for toxicity following Irinotecan administration, due to the presence of elevated levels of unconjugated SN-38. Decreased UGT1A1 activity can result from mutations in the coding sequence of the UGT1A1 gene, which alter the structure of the encoded protein, or from decreased expression of the normal protein product. A common cause of decreased expression levels of UGT1A1 is a variation in the number of TA repeats in the TATA box of the UGT1A1 gene promoter. The (TA)6 (i.e., 6 TA repeats) version of the promoter is considered to be the "normal" or wild type. Compared to the (TA)6 promoter, the (TA)7 version has a decreased activity, leading to the production of lower levels of UGT1A1 transcripts. To date, alleles containing 5, 6, 7, and 8 TA repeats have been identified. Several clinical studies have shown that individuals who are homozygous, and potentially those who are heterozygous, for the UGT1A1 (TA)7 promoter allele (UGT1A1*28) are at increased risk for the development of a significant adverse response to the standard dose of Irinotecan. Therefore, in July of 2005, the FDA altered the package labeling of Irinotecan to suggest a lower starting dose of Irinotecan for patients known to be homozygous for the UGT1A1 *28 (i.e., 7 TA repeat) allele.