Novel fluoropyrimidines:improving the efficacy and tolerability of cytotoxic therapy

The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphism's and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such inter-individual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.