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Thymidylate synthase inhibitors

N Touroutoglou1, R Pazdur

  • 1Division of Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 1, 1996
PubMed
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Selective thymidylate synthase (TS) inhibitors show promise in cancer treatment. Their efficacy depends on cellular uptake via the reduced folate carrier (RFC) and polyglutamation, with ongoing research exploring new compounds and overcoming resistance mechanisms.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Thymidylate synthase (TS) is a critical enzyme in DNA synthesis, making it a target for cancer chemotherapy.
  • Folate analogues have been developed to selectively inhibit TS, leveraging molecular structures and properties for targeted action.

Purpose of the Study:

  • To review the structure-activity relationship, development, and future prospects of selective TS inhibitors.
  • To discuss the mechanisms of cellular entry and intracellular processing of these novel anticancer agents.

Main Methods:

  • Review of preclinical and clinical data for various TS inhibitors, including CB3717, ZD1694 (Tomudex), LY231514, ZD9331, 1843U89, AG337, and AG331.
  • Analysis of the role of the reduced folate carrier (RFC) and polyglutamation in TS inhibitor activity and cellular retention.

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Main Results:

  • Early TS inhibitor CB3717 showed antineoplastic activity but was limited by nephrotoxicity.
  • ZD1694 (Tomudex) demonstrated efficacy in colorectal, breast, and pancreatic cancers and completed Phase III trials.
  • Other compounds like LY231514, ZD9331, 1843U89, AG337, and AG331 are in various stages of development, with some designed for RFC independence.

Conclusions:

  • Selective TS inhibitors represent a promising class of anticancer drugs, with varying mechanisms of action and clinical development pathways.
  • Future success may depend on overcoming cellular resistance mechanisms and potentially combining TS inhibitors with other therapeutic agents.