ZD1694 (TOMUDEX) - A NEW THYMIDYLATE SYNTHASE INHIBITOR WITH ACTIVITYIN COLORECTAL-CANCER

ZD1694 (Tomudex) is a new antifolate which is a specific inhibitor of thymidylate synthase (TS). Evidence suggests that ZD1694 has a spectru m of activity that only partially overlaps with 5-fluorouracil (modula ted with leucovorin) against colon tumours in vitro. Potent cytotoxic activity is dependent upon active uptake into cells via the reduced fo late/methotrexate cell membrane carrier (RFC) and subsequent metabolis m to polyglutamated forms (tri, tetra and pentaglutamates). These poly glutamates are approximately 60-fold more active as TS inhibitors and are not effluxed readily from cells. Extensive polyglutamation also oc curs in various mouse tissues (e.g. small intestinal epithelium, liver and kidney), resulting in high tissue/plasma drug ratios which persis t for a prolonged period. ZD1694 has antitumour activity in mice, alth ough the high plasma thymidine in this species complicates: (1) the in terpretation of therapeutic index; (2) tumour types in which activity is likely to be observed; and (3) translation of doses and schedules f or clinical evaluation. ZD1694 entered clinical study and has complete d Phase I and II evaluation, with activity observed in several tumour types. Appreciable activity in the Phase II colorectal study (29% obje ctive response fate on interim analysis) led to the current Phase III study, randomised against 5-fluorouracil/leucovorin.