Leading Article: Oncologic, Endocrine & Metabolic: New antimetabolites in preclinical and clinical development

Abstract

A number of new antimetabolites successfully entered clinical practice over the last ten years, and several more are awaiting registration in a number of countries. In addition, several compounds have been developed for use in combination with established anticancer agents (primarily 5-fluorouracil [5-FU] or one of its analogues). The most successful group of new anticancer agents are the deoxynucleoside analogues (e.g., cladribine, fludarabine, 5-aza-2′-deoxycytidine and gemcitabine), which require activation by one of the four deoxynucleoside kinases present in mammalian cells. However, a further analogue, pentostatin, is a potent inhibitor of adenosine deaminase, leading to an increase in deoxyadenosine, which becomes toxic after conversion to the deoxynucleotide. Other interesting compounds require activation by a viral deoxynucleoside kinase; the Herpes Simplex Virus (HSV)-thymidine kinase (TK), e.g., ganciclovir. A number of compounds have been developed to modulate the activity of 5-FU, e.g., ethynyluracil (EU) and 5-chloro-2,4-dihydroxypyridine (CDHP) inhibit dihydropyrimidine dehydrogenase (DPD), thus, preventing degradation of 5-FU and increasing its bioavailability. Prodrugs of 5-FU have attracted much more attention recently than in the 1980s: e.g., ftorafur, present in (UFT) [1-(2-tetrahydrofuryl)-5-fluorouracil:uracil (1:4)] and S-1, and capecitabine, a prodrug of the 5-FU precursor 5′-deoxy-5-fluorouridine. Antifolates have also received a lot of attention and several new antifolates have been developed over the last ten years, of which the most interesting are the new thymidylate synthase (TS) inhibitors. Many of these have entered clinical development and some have even been registered (e.g., tomudex in England). These compounds include tomudex (ZD1694, formerly ICI-D1694; Zeneca), LY231514 (Eli Lilly), 1843U89 (formerly BW1843U89; Glaxo Wellcome), and AG331 and AG337 (Thymitaq; Agouron). AG337 is of special interest, since it appears to exhibit a different pattern of activity to that of tomudex. A new group of antifolates in development, and generating considerable interest, are the glycinamide ribonucleotide transferase (GARTF) inhibitors: e.g., lometrexol and LY309887 (Eli Lilly), and AG2032 and AG2034 (Agouron). However, the place of these compounds in therapy (i.e., as single agents or as modulating agents) remains unclear at present. In summary, rational drug design over the last few decades has led to the introduction of a number of antimetabolites with significant antitumour activity not only against leukaemia, but also against several solid tumours.