Testing prior to beginning Irinocetan chemotherapy.
Irinotecan Toxicity UGT1A
Clinical Features
Irinotecan (CPT-11) is a cytostatic agent often used in the treatment of colorectal cancer. Irinocetan is metabolised in the body by hydrolysis into its active metabolite SN-38, which is then conjugated with its beta-glucuronid and made inactive through the process of Uridine Diphosphate Glucoronosyltransferase 1A1 (UGT1A1). There are more than 30 different known promoter mutations responsible for causing UGT1A1 enzyme inactivity (e.g. Crigler-Najjar and Gilbert syndromes). Patients with reduced UGT1A1 have a heightened risk of suffering irinocetan-induced poisoning.
Genetic Information
Gilbert Syndrome is an autosomal recessive inherited synthesis defect caused by an expansion of dinucleotide repeats (TA; 6 repeats are normal: TA 6) in the regulatory (promoter) region of the UGT1A1 gene located on chromosome 2 (2q37). In approximately 80% of cases, this expansion (TA 7) is found in homozygous form, i.e. on both alleles. In approximately 20% of affected patients, the expansion is found on only one allele. The prevalence of persons with a homozygous expansion is greater than the number of patients displaying a clinical manifestation of Gilbert Syndrome.
Prevalence
The prevalence of homozygous carriers is approx. 1:10. The prevalence of the clinical manifestation of Gilbert Syndrome is lower; men are more often affected than women.
Diagnostic
Indication
Method
Normal alleles (TA 6) and expanded alleles (TA 7) are detected using PCR and fragment-length analysis.
Sample Requirement
2 - 4 ml of EDTA blood; in some cases, an oral swab
Duration
3 days