Clinical implications of 5-FU modulation

Abstract

In recent years, due to the advent of sensitive instrumentation and methodologies, it has been possible to identify parameters that predict the quality of response of individual patients to treatments for specific selected diseases, e.g., colon carcinoma and breast carcinoma. Ongoing studies are attempting to identify sensitive patients in order to select treatment regimens suitable for the individual patient. The critical question that remains is whether the basis for drug resistance is due in part to insufficient delivery of drugs to target tumor cells or to the resistance of target tumor cells by various mechanisms, including, in the case of 5-fluorouracil (5-FU), drug transport, metabolism, expression of the target enzyme thymidylate synthase (dTMPS), depletion of folate cofactors, and/or level of competing substrate deoxyuridine monophosphate. Also in recent years, attempts have been made to delineate mechanisms of resistance to the fluoropyrimidines. On the basis of such studies, it may be possible to develop approaches aimed at the selective modulation of the therapeutic efficacy of these agents in tumor tissues with varying degrees of sensitivity of fluoropyrimidines, e.g., patients with advanced colorectal cancer. One such approach is the use of calcium folinate to modulate the therapeutic efficacy of 5-FU.