Pharmacogenomics of Tamoxifen and Irinotecan Therapies

Genetic variability in drugmetabolizing enzymes affects the toxicity and efficacy of many compounds, including the chemotherapeutic agents irinotecan and tamoxifen. The correlation of clinical response to polymorphisms in enzymes associated with metabolism of these two drugs has led to the recommendation that patients who receive them undergo genotyping analysis. Irinotecan toxicity in patients who have colorectal cancer has been linked to reduced activity of uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1). Reduced cytochrome P450 (CYP) 2D6 activity leads to therapeutic failure of tamoxifen in the prevention and treatment of breast cancer, as a result of absence of conversion of the prodrug to its active forms. This article discusses current knowledge of the usefulness of UGT1A1 and CYP2D6 genotyping in the context of cancer chemotherapy and highlights the need for additional studies to clarify the many issues remaining.