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Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors
Y M Rustum1, A Harstrick, S Cao
1Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Purpose And Methods:
Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694.
Results:
Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU.
Conclusion:
In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.
Insights
Direct thymidylate synthase (TS) inhibitors show similar efficacy to fluorouracil/leucovorin (5-FU/LV) in colorectal cancer but with reduced toxicity. Further research explores novel TS inhibitors and DPD enzyme modulators to improve cancer therapy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Fluoropyrimidines like fluorouracil (5-FU) are used in cancer therapy but face limitations in selectivity, resistance, and efficacy.
- Leucovorin (LV) modulation improves the efficacy of fluoropyrimidines by targeting thymidylate synthase (TS).
Purpose of the Study:
- To review the current status of direct and indirect thymidylate synthase (TS) inhibitors.
- To discuss the future prospects of novel TS inhibitors in cancer treatment, particularly for colorectal cancer.
Main Methods:
- Preclinical and clinical evaluations of direct TS inhibitors (e.g., ZD1694, AG337, LY231514).
- Phase III comparative study of a direct TS inhibitor (ZD1694) versus an indirect inhibitor (5-FU/LV).
- Investigation of dihydropyrimidine dehydrogenase (DPD) inhibitors to enhance 5-FU therapeutic index.
Main Results:
- Direct TS inhibitors demonstrate potent and specific activity against TS.
- A Phase III trial showed ZD1694 has similar efficacy to 5-FU/LV but with reduced toxicity.
- DPD enzyme inactivation of 5-FU leads to toxicity, prompting the development of DPD inhibitors.
Conclusions:
- Direct and indirect TS inhibitors offer comparable therapeutic activity.
- Newer TS inhibitors may provide an improved toxicity profile.
- Further development of TS inhibitors and DPD modulators holds promise for improved cancer therapies.