Potential for predicting toxicity and response of fluoropyrimidines in patients

The efficacy of cancer therapy is compromised by the fact that there are currently no goood ways to predict which patients will benefit from treatment. This long standing goal is closer to becoming a reality as more is learned about the molecules that affect the activities of various therapeutic agents. The fluoropyrimidine antimetabolites drugs have been in clinical use for over 4 decades and the cellular proteins important for their activities have been studied in detail. The most important are the major target enzyme, thymidylate synthase (TS) and the rate limiting enzyme in the degradation pathway, dihydropyrimidine dehydrogenase (DPD), equally important for the analogue capecitabine is thymidine phosphorylase (TP), which is rate limiting for activation of this prodrug. A number of assays are available for these enzymes, including enzyme activity measurements, quantitative PCR for RNA expression and immunological methods for protein expression. With each of these methods, more clinical studies are required to validate their clinical usefulness.