Irinotecan pharmacogenetics: is it time to intervene?

The development of unpredictable systemic toxicity while attempting to achieve tumor response has been a common observation for as long as there has been anticancer therapy. The narrow therapeutic index of most chemotherapeutic agents and the severe consequences of both undertreatment and overdosing have led to a pressing need for molecular predictors of the toxicity and efficacy of cancer treatments. In the days when there were few options for the treatment of most human malignancies, it was acceptable to tolerate grade 4 toxicities in as many as 10% of patients in the search for optimal dose-intensity. Better that a patient experience side effects than the tumor be undertreated. However, much progress has been made in treating human malignancies, and there are now multiple treatment options with similar efficacy for nearly every type of cancer. Ideally, patients should receive a regimen that offers optimal efficacy with minimal chance of severe side effects. This can only be accomplished if there are means to determine the relative risks of both patient benefit and toxicity. In the context of regimens demonstrating similar efficacy in large populations of patients, but showing no individual predictive markers of benefit, toxicity prediction would be a meaningful way to achieve the goal of better therapy for individual patients. Irinotecan is an excellent candidate for individualized therapy. The drug has demonstrated potent activity against many types of human cancer, in particular, gastrointestinal and pulmonary malignancies. Indeed, the addition of irinotecan to first-line therapy with fluorouracil and leucovorin has led to improved survival in patients with advanced colorectal cancer. However, irinotecan does have significant side effects, including both acute and delayed diarrhea, neutropenia, and a vascular syndrome. The gastrointestinal and vascular syndromes have been associated with a high mortality rate in patients receiving the combination of irinotecan with bolus fluorouracil and leucovorin during the first 60 days of therapy. There are now combination therapy regimens with equal or superior efficacy, such as infusional fluorouracil and leucovorin with irinotecan or oxaliplatin. Hence the conundrum: can we identify patients who will receive antitumor benefit from irinotecan without experiencing severe, life-threatening, or fatal toxicity? Irinotecan is among the camptothecin class of topoisomerase 1 inhibitors. It is a prodrug and must be converted to SN-38 by carboxylesterase 2, resulting in a greater than 1,000-fold enhancement of cytotoxic activity. Before activation, irinotecan must run a disposition gauntlet of oxidation by cytochrome p450 enzymes, and transport by adenosine triphosphate– binding cassette efflux pumps. SN-38 must also undergo one of three fates: binding to the cellular target topoisomerase 1, exclusion from the cell via efflux pumps, or inactivation by the addition of a glucuronide moiety. While each of these steps has the potential to substantially regulate irinotecan activity, it is glucuronidation by the protein UGT1A1 that has the clearest potential impact on patient care. The glucuronidation of lipophilic compounds is catalyzed in vertebrates by the uradine diphosphate– glucuronosyltransferases (UGTs). This catalytic reaction utilizes UDP-glucuronic acid as a cosubstrate for the formation of glucuronides from various substrates, such as bilirubin, hormones, drugs, and other xenobiotics. This reaction leads to the formation of hydrophilic glucuronides from lipophilic substrates, facilitating the transport of these molecules to aqueous compartments of the body, and leading to elimination through the bile and urine. UGT glucuronidation is consequently regarded as a “detoxification” reaction, and UGTs therefore represent major phase II drug metabolizing enzymes. More than 16 human UGTs have been characterized and divided into two families—UGT1 and UGT2. All known family-1 members are encoded by the UGT1A locus JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 8 APRIL 15 2004