5-Fluorouracil (5-FU): A Cancer Chemotherapy Drug

Although introduced as a chemotherapy agent almost 45 years ago, 5-fluorouracil (5-FU) remains one of the most successful and widely used cancer chemotherapy drugs. 5-FU can be used as a single agent but is typically administered in combination with other drugs for the treatment of a number of different malignancies including carcinomas of the breast, colon, and skin (three of the most frequently occurring cancers). In general, 5-FU is relatively well tolerated at standard doses with typical toxic effects occurring in the gastrointestinal mucosa and bone marrow. Neurologic toxicity presenting as cerebellar ataxia and somnolence occurs much less frequently (<5%). Like many other antineoplastic drugs, 5-FU has a relatively narrow therapeutic window, such that toxicity is likely to increase as the dose is increased. The success of 5-FU has led to several new generation 5-FU-based drugs including Xeloda (Roche) and Tegafur (Taiho).

5-FU: Effects and Toxicity

The anticancer effects and toxicity of 5-FU are directly related to anabolism of the drug to its nucleotides, which can then exert effects through inhibition of thymidylate synthase activity or incorporation into RNA and/or DNA. In humans, more than 85% of an administered dose of 5-FU is degraded through the catabolic pathway. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting step in pyrimidine catabolism. Over the last decade, it has become clear that DPD regulates the amount of 5-FU available for anabolism thereby affecting its pharmacokinetics, toxicity, and efficacy.

Unanticipated Toxicity to 5-FU

Several reports have described an inherited (pharmacogenetic) disorder in which individuals with absent or significantly decreased DPD activity develop life-threatening toxicity following exposure to 5-FU. Since the catabolic pathway does not function in DPD deficient patients, administration of standard doses of 5-FU results in altered 5-FU pharmacokinetics and severe toxicity including mucositis, granulocytopenia, neuropathy and death. The cause for this toxicity appears to be decreased drug clearance, resulting in markedly prolonged exposure to 5-FU. It has been estimated that approximately 3-5% of the population has DPD activity less than 95% of the lower limit (<0.064 nmol/min/mg for frozen samples) for the normal population. Recent studies by our laboratory have demonstrated a large over-representation of both profoundly (12 %) and partially (31%) DPD deficient patients who developed unanticipated toxicity following treatment with 5-FU.