Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity.

AIMS: To examine retrospectively the relationship between DPD phenotype/genotype and the intensity of 5FU toxicity. METHODS: One hundred and thirty-one case-reports (81 women, 50 men) with 5FU-related toxicity were analyzed. RESULTS: The lower the DPD activity (10-504 pmol min(-1) mg(-1)), the higher the toxicity grade was scored (P < 0.01). Toxicity-related deaths occurred in nine patients (eight women) who significantly expressed lower DPD activity than other patients. Two of the deceased patients had normal DPD activity. The IVS14+1G>A mutation, analyzed in 93 patients, was detected in two patients (nonlethal toxicity). CONCLUSIONS: The IVS14+1G>A mutation may not help prevent toxicity and patients with normal DPD activity may develop life-threatening 5FU toxicity.

Pharmacogenetic influences on treatment response and toxicity in colorectal cancer.

Current use of chemotherapeutic and targeted agents for advanced colorectal cancer (CRC) results in high tumor response rates and relatively long overall patient survival. Fluoropyrimidines, irinotecan, and oxaliplatin are highly active in first-line and salvage therapy of colorectal cancer. Targeted therapies, including anti-angiogenesis agents and anti-epidermal growth factor receptor antibodies, have been incorporated with traditional chemotherapy and offer additional options for patients with CRC. However, there is marked variability in response to therapy, as well as frequency and severity of toxicities. Molecular markers and pharmacogenomic profiling may improve prediction of patients who will experience significant benefit or toxicity from currently available agents. Validation of these predictive factors in prospective clinical trials is now necessary to allow for a rational and systematic individualization of cancer therapy.