New targets for pyrimidine antimetabolites in the treatment of solid tumours. 1: Thymidylate synthase.
Thymidylate synthase forms the target for anticancer therapy with fluoropyrimidines. Anticancer activity can be increased by the use of different modulators of fluoropyrimidine metabolism, which lead to an enhanced inhibition of thymidylate synthase. In vitro and in vivo studies with fluoropyrimidines and two of these modulators, folinic acid (leucovorin) and interferon, are summarized. The promise of these preclinical results is reflected by the response data of several clinical trials. The biochemical effects of these modulators are described and illustrated by the fluoropyrimidine-mediated inhibition of thymidylate synthase in tumour samples, which is clearly enhanced by folinic acid. The regulation of thymidylate synthase synthesis may also be crucial for total blockade of thymidylate synthase activity. This regulation may be influenced by interferon-gamma. Although the addition of modulators increases the activity of fluoropyrimidines at the level of thymidylate synthase, most solid tumours, especially colorectal carcinomas, are resistant to these combinations. For this reason, new, more potent inhibitors of thymidylate synthase have been developed, the antifolates. Preclinical data show that some of these compounds have good antitumour activity, but they still have to prove their value in the clinic. These two approaches, the use of modulators and new compounds, have shown activity preclinically and the extension of these findings to clinical studies stresses the importance of thymidylate synthase as a target in fluoropyrimidine therapy of solid tumours.