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ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer
A L Jackman1, D C Farrugia, W Gibson
1CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
ZD1694 (Tomudex) is a new antifolate which is a specific inhibitor of thymidylate synthase (TS). Evidence suggests that ZD1694 has a spectrum of activity that only partially overlaps with 5-fluorouracil (modulated with leucovorin) against colon tumours in vitro. Potent cytotoxic activity is dependent upon active uptake into cells via the reduced folate/methotrexate cell membrane carrier (RFC) and subsequent metabolism to polyglutamated forms (tri, tetra and pentaglutamates). These polyglutamates are approximately 60-fold more active as TS inhibitors and are not effluxed readily from cells. Extensive polyglutamation also occurs in various mouse tissues (e.g. small intestinal epithelium, liver and kidney), resulting in high tissue/plasma drug ratios which persist for a prolonged period. ZD1694 has antitumour activity in mice, although the high plasma thymidine in this species complicates: (1) the interpretation of therapeutic index; (2) tumour types in which activity is likely to be observed; and (3) translation of doses and schedules for clinical evaluation. ZD1694 entered clinical study and has completed Phase I and II evaluation, with activity observed in several tumour types. Appreciable activity in the Phase II colorectal study (29% objective response rate on interim analysis) led to the current Phase III study, randomised against 5-fluorouracil/leucovorin.
Insights
ZD1694 (Tomudex), an antifolate drug, shows promise as a thymidylate synthase inhibitor. Its unique polyglutamation mechanism enhances cytotoxic activity, leading to promising results in colorectal cancer clinical trials.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- ZD1694 (Tomudex) is a novel antifolate agent targeting thymidylate synthase (TS).
- Its mechanism of action involves cellular uptake via the reduced folate/methotrexate carrier (RFC) and intracellular polyglutamation.
- Polyglutamated forms exhibit significantly enhanced TS inhibition and reduced efflux compared to the parent drug.
Purpose of the Study:
- To evaluate the activity spectrum of ZD1694 compared to 5-fluorouracil in colon tumors.
- To investigate the role of cellular uptake and polyglutamation in ZD1694's potent cytotoxic activity.
- To assess the antitumour activity and clinical efficacy of ZD1694 in various cancer types.
Main Methods:
- In vitro studies to assess activity against colon tumors.
- Pharmacokinetic analysis of ZD1694 uptake and polyglutamation in cellular and animal models.
- Phase I, II, and III clinical trials to evaluate safety, efficacy, and response rates in cancer patients.
Main Results:
- ZD1694 demonstrates a partially overlapping activity spectrum with 5-fluorouracil against colon tumors in vitro.
- Extensive polyglutamation in mouse tissues leads to high drug concentrations and prolonged retention.
- Phase II trials showed appreciable activity in colorectal cancer (29% objective response rate), prompting Phase III investigation.
Conclusions:
- ZD1694's potent cytotoxicity is mediated by intracellular polyglutamation, enhancing TS inhibition.
- Despite complexities in animal models, ZD1694 exhibits antitumour activity and has completed Phase I/II clinical evaluations.
- Promising Phase II results in colorectal cancer have led to a Phase III randomized trial against 5-fluorouracil/leucovorin.