Tomudex(TM) (ZD1694): From concept to care, a programme in rational drug discovery

Folate-based anticancer drugs with specificity for thymidylate synthase (TS) have come of age. Ideas nurtured in the early 1970s led to the first-generation of antifolates with TS and dihydrofolate reductase (DHFR) inhibitory activities. Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR). CB3717 had significant clinical activity but its development had to be abandoned because its low aqueous solubility led to occasional nephrotoxicity. Collaborative laboratory studies between the ICR and ICI Pharmaceuticals (later to become Zeneca Pharmaceuticals) led to the discovery of ZD1694 (Tomudex(TM)), the first antifolate to be licensed for the treatment of cancer (UK 1995) in nearly 40 years and the first new drug for colorectal cancer in about 35 years. Tomudex belongs to a class of compounds that use the reduced-folate carrier (RFC) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase (FPGS). This paper reviews the underlying philosophies, and the milestones reached during the development of Tomudex.