Irinotecan toxicity ... (irinotecan toxicity) - Gen UGT1A1

Irinotecan, also known as CPT-11, is an analog of camptothecin commonly used in the treatment of metastatic colorectal cancer, alone or in combination with 5-fluorouracil - see toxicity Fluorouracil - DPYD- gene and folic acid . It is also used for treatment of breast cancer and gastric adenocarcinomas. Its mode of action involves the specific inhibition of DNA topoisomerase I (TOP I) by its principal cytotoxic metabolite, SN-38, blocking DNA replication.

SN-38 is inactivated mainly in the liver by the enzyme bilirubin UDP-glucuronasiltransferasa 1A1 (bilirubin-UGT 1). This enzyme is encoded from UGT1A1 gene, located on the long arm of chromosome 2 (2q37), so some genetic alterations in sequence could generate partial or complete inactivation of the enzyme bilirubin-UGT 1, resulting in the hereditary diseases, autosomal recessive, known as Crigler-Najjar syndrome and Gilbert syndrome - see Crigler-Najjar syndrome ..., Gilbert syndrome ... - Gen UGT1A1-.

The mildest and usual Gilbert syndrome is characterized by mild hyperbilirubinemia caused by mutations that lead to reduced levels of gene expression. Insertions usually are promoter ( "TATA-box") UGT1A1 gene. The "TATA-box" consists of six base pair repeats TA. Individuals with Gilbert syndrome have seven homozygous TA repeats and, in some more minority and / or people from Africa cases described five or eight pairs of TA repeats. On occasion it has also located some point mutation, such as Gly71Arg or G71R, causing a moderate reduction in activity of bilirubin-UGT 1, resulting in mild hyperbilirubinemia.

If irinotecan treatment, individuals with these disorders may be high toxicity and increased adverse reactions often consist of severe gastroenteritis, leucopenia / neutropenia, nausea, vomiting, and alopecia cholinergic syndrome. However, it appears that these mutations based inserts promoter explain only part of the toxic reactions, so there may be other nucleotide changes in the rest of the coding region of the UGT1A1 gene affecting irinotecan toxicity.

The identification of mutations in the UGT1A1 gene facilitates identification susceptible to effects of toxicity to irinotecan patients and allows the search for alternative prior treatments even starting treatment if the study of mutations has been done in previous form , as it would be recommended.

Tests in IVAMI: IVAMI performed in detecting mutations in the UGT1A1 gene by the complete PCR amplification of the gene exons and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).