Genetic alterations help predict severe side effects related to irinotecan

June 1, 2003

The presence of specific gene alterations can help doctors predict which colorectal cancer patients are likely to experience severe side effects from the new chemotherapy drug irinotecan, new research shows. Patients with these alterations who receive irinotecan are more likely to experience low white blood cell counts, which can lead to serious--and in some cases life-threatening--infections.

"The study's results underscore the need to identify patients genetically predisposed to severe side effects from irinotecan treatment," said Mark J. Ratain, MD, of the University of Chicago Medical Center, the study's lead investigator. "Those patients could be given reduced doses of irinotecan or other chemotherapy drugs."

In the body, irinotecan is converted into the active form of the drug, called SN-38. The alterations occur in a gene that is responsible for the production of the UGT1A1 enzyme. This enzyme helps protect normal, healthy cells from the toxic effects of irinotecan by converting SN-38 into an inactive compound. A defect in the UGT1A1 gene increases the likelihood that healthy cells will be damaged by prolonged exposure to SN-38.

The UGT1A1 gene exists in two forms--6 and 7. The 7 form is associated with a reduced ability to protect healthy cells from the toxic effects of irinotecan.

In the study of 61 patients treated with irinotecan, 8% experienced a severe drop in the number of white blood cells, a condition called neutropenia. Patients with a 7/7 genotype were most likely to experience severe neutropenia, the researchers found. None of the patients with 6/6 genotype developed neutropenia, and only a few of the patients with the 6/7 genotype had neutropenia.

A screening test to detect defects in the UGT1A1 gene is not yet commercially available, but patients can get the test at the University of Chicago Medical Center. Dr. Ratain estimated that a screening test would become more widely available within the next two years.