Irinotecan Toxicity Detection Assay for Gel Electrophoresis

Irinotecan Toxicity Detection Assay for Real-Time PCR

This is a comprehensive predictive test available for assessing the risk of toxicity due to Irinotecan-based chemotherapy which was approved by FDA as the 1st line (with 5-FU and leucovorin) and 2nd line therapy for metastatic colon/rectal cancer. It detects polymorphic variants of UGT1A1 that cause increase toxicity associated with Irinotecan.

FDA Guidance. Studies have identified a genetic variant of the UGT1A1 gene that is commonly associated with severe toxicity in cancer patients undergoing Irinotecan-based therapy. In 2005 FDA cleared a test for UGT1A1 that detects this genetic variant, helping physicians determine the appropriate dosage of the drug with minimum adverse effects.

Functional roles of UGT1A1. Uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) is an enzyme that catalyzes the glucuronidation of various compounds, including steroid hormones, bilirubin, as well as xenobiotics, such as irinotecan. This process converts these substances to more water-soluble compounds that can be eliminated from the body.¹ A polymorphic variation in the promoter of UGT1A1 leads to decreased expression of UGT1A1, resulting in reduced glucuronidation of SN-38, the active metabolite of irinotecan.² Patients with a (TA)₇ repeat (UGT1A1*28) have a 12-50% increased risk of Grade 4 neutropenia or severe diarrhea.^3,4 Individuals that are homozygous for UGT1A1*28 mutation, that is have two alleles with 7 TA repeats (7/7 homozygous) also known as a Gilbert's syndrome, will have the most severe toxicity to irinotecan.⁵

UGT1A1*28-associated risk of neutropenia:

Reporting. This assay tests for two polymorphic variations in the promoter region of UGT1A1: UGT1A1*1 (TA)₆ and UGT1A1*28 (TA)₇.

Interpretation. Patients in the High Risk and Moderate Risk groups carry a 50% and 12.5% risk of severe (Grade 4) neutropenia, respectively. A dose reduction of irinotecan should be considered.

Other names for irinotecan drugs:
Camptosar^®, CPT-11

Disclaimer
EntroGen provides reagents that are offered to clinical laboratories in order to simplify the development of in-house validated clinical diagnostic tests. Not cleared by FDA for IVD use.

References

1. Rouits et al., Clin Cancer Res. 2004; 10:5151-5159
2. Iyer et al., J Clin Invest. 1998; 101:847-854
3. Proceedings from FDA Clinical Pharmacology Subcommittee, November 3-4, 2004. (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4079B1_03_Topic1-TabA.pdf)
4. Innocenti et al., J Clin Oncol. 2004; 22:1382-1388
5. Beutler et al., Proc Natl Acad Sci USA. 1998; 95:8170-8174