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ZD9331

Preclinical and Clinical Studies

  • Chapter
Antifolate Drugs in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Thymidylate synthase (TS) has been the target enzyme for intensive antifolate drug development for several years and specific inhibition of TS, and hence DNA synthesis, has been achieved with a range of quinazoline analogs of folic acid, including CB3717 (1–3) and its non-nephrotoxic successor, TomudexTM (ZD1694, raltitrexed) (4–6). The latter compound has recently been introduced in a number of counties for the treatment of advanced colorectal cancer and is reviewed by Hughes et al. and Beale et al. (see Chapters 6 and 7). ZD1694 is a polyglutamatable drug that depends on cellular uptake via a carrier-mediated, saturable mechanism (the reduced-folate carrier; RFC) (7–13). ZD1694 polyglutamates are significantly more potent TS inhibitors than the parent drug and retention of high-chain-length forms inside cells results in prolonged inhibition of TS in tumor cells grown in vitro and in vivo. Of more recent interest has been the development of water-soluble acidic, quinazoline-based TS inhibitors that lack FPGS substrate activity but retain high affmity for the RFC. Work from the group of F. Sirotnak (14) has provided evidence that compounds with favorable kinetic parameters for the RFC may offer a tumor-selective advantage, at least in murine models. Additionally, our own research demonstrated a clear potency advantage of compounds that use the RFC. Such compounds would be expected to be active against tumors expressing low FPGS or high folylpolyglutamyl hydrolase (FPGH) activity, both documented mechanisms of resistance in cell lines with acquired resistance to polyglutamatable antifolates (7–13); and give a different, and possibly more controllable, toxicity profile than ZD1694. Whereas examples of antifolates with these biochemical attributes already existed when we started the program, e.g., the water-soluble, nonpolyglutamatable inhibitors of DHFR, none have reached the stage of clinical evaluation (15–17).

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Authors
  1. F. Thomas Boyle
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  2. Trevor C. Stephens
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  3. S. D. Averbuch
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  4. Ann L. Jackman
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Editor information

Editors and Affiliations

  1. The Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    Ann L. Jackman

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© 1999 Springer Science+Business Media New York

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Boyle, F.T., Stephens, T.C., Averbuch, S.D., Jackman, A.L. (1999). ZD9331. In: Jackman, A.L. (eds) Antifolate Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-725-3_11

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  • DOI: https://doi.org/10.1007/978-1-59259-725-3_11

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-4521-4

  • Online ISBN: 978-1-59259-725-3

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