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ZD9331: discovery to clinical development.

T S Benepal1, I Judson

  • 1Royal Marsden Hospital NHS Trust, Sutton, Surrey UK. tim.benepal@rmh.nthames.nhs.uk

Anti-Cancer Drugs
|December 23, 2004
PubMed
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ZD9331, a novel thymidylate synthase inhibitor, shows promise in treating various cancers without polyglutamation. This cancer drug may reduce toxicity and overcome resistance, particularly in ovarian, pancreatic, and gastric cancers.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Therapeutics

Background:

  • Thymidylate synthase (TS) is a validated target in cancer therapy.
  • Previous TS inhibitors, like raltitrexed, require polyglutamation for activity.
  • Reduced expression of folylpolyglutamate synthetase (FPGS) can lead to resistance against polyglutamatable drugs.

Purpose of the Study:

  • To evaluate ZD9331, a third-generation TS inhibitor designed for non-polyglutamation.
  • To overcome resistance mechanisms associated with FPGS.
  • To potentially reduce toxicities linked to polyglutamation and drug retention.

Main Methods:

  • Preclinical studies assessed ZD9331 transport via reduced folate carrier and alpha-folate receptor.
  • In vivo studies demonstrated broad anti-cancer activity.

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  • Extensive Phase I clinical trials were conducted across various administration schedules.

    • Main Results:

    • ZD9331 demonstrated promising activity in platinum-refractory relapsed ovarian, pancreatic, and gastric cancers.
    • The drug is transported by both reduced folate carrier and alpha-folate receptor.
    • Monotherapy and combination studies showed encouraging outcomes.

    Conclusions:

    • ZD9331 represents a novel approach to TS inhibition, potentially offering improved efficacy and safety.
    • Patient selection based on folate transport and FPGS status may enhance therapeutic potential.
    • Further investigation is warranted to determine the full clinical utility of ZD9331.