RESISTANCE TO 5-FLUOROURACIL

1. Primary and secondary resistance to the widely used antimetabolite 5-fluorouracil (5-FU) are common phenomena in cancer chemotherapy. Bec ause 5 FU still remains the agent of choice in the treatment of, for e xample, colorectal cancer, circumvention of resistance is of vital imp ortance. 2. Resistance to fluoropyrimidines is a multifactorial event, which includes transport mechanisms, metabolism, molecular mechanisms , protection from apoptosis, and resistance via cell cycle kinetics. T o date, the prediction of primary resistance to 5-FU in the clinic is limited to few studies focusing mainly on the key enzyme thymidylate s ynthase. To gain a deeper insight into the key events responsible for 5-FU resistance in vivo, the evaluation of additional parameters such as other (fluoro)pyrimidine converting enzymes, the mutational status of regulators of apoptosis, and tumour angiogenesis is currently under investigation. 3. Most studies on the circumvention of fluoropyrimidi ne resistance refer to preclinical investigations and were rarely conf irmed in clinical trials. Although our understanding of resistance to 5-FU leaves many open questions, the fundamental insights accomplished during the last years provide a rational understanding to exceed the bounds of the actual therapeutic schedules. (C) 1998 Elsevier Science Inc.