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Tomudex (ZD1694): from concept to care, a programme in rational drug discovery
A L Jackman1, F T Boyle, K R Harrap
1CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
Folate-based anticancer drugs with specificity for thymidylate synthase (TS) have come of age. Ideas nurtured in the early 1970s led to the first-generation of antifolates with TS and dihydrofolate reductase (DHFR) inhibitory activities. Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR). CB3717 had significant clinical activity but its development had to be abandoned because its low aqueous solubility led to occasional nephrotoxicity. Collaborative laboratory studies between the ICR and ICI Pharmaceuticals (later to become Zeneca Pharmaceuticals) led to the discovery of ZD1694 (Tomudex), the first antifolate to be licensed for the treatment of cancer (UK 1995) in nearly 40 years and the first new drug for colorectal cancer in about 35 years. Tomudex belongs to a class of compounds that use the reduced-folate carrier (RFC) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase (FPGS). This paper reviews the underlying philosophies, and the milestones reached during the development of Tomudex.
Insights
The development of Tomudex (ZD1694), a targeted antifolate drug, represents a significant advancement in cancer therapy. This drug specifically inhibits thymidylate synthase (TS), offering a new treatment for colorectal cancer.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Folate-based anticancer drugs targeting thymidylate synthase (TS) have evolved significantly since the 1970s.
- Early antifolates inhibited both TS and dihydrofolate reductase (DHFR).
- CB3717, a selective TS inhibitor, showed clinical activity but faced development challenges due to poor solubility and nephrotoxicity.
Purpose of the Study:
- To review the development of ZD1694 (Tomudex), an antifolate drug.
- To highlight the scientific philosophies and key milestones in Tomudex's journey from concept to licensure.
- To discuss the drug's mechanism of action involving the reduced-folate carrier (RFC) and folylpolyglutamate synthetase (FPGS).
Main Methods:
- Review of historical research and development data.
- Analysis of drug discovery collaborations between the Institute of Cancer Research (ICR) and ICI Pharmaceuticals (Zeneca).
- Examination of the chemical properties and biological activity of CB3717 and ZD1694.
Main Results:
- ZD1694 (Tomudex) was discovered through collaborative efforts, addressing the limitations of earlier compounds.
- Tomudex became the first antifolate licensed for cancer treatment in the UK in nearly 40 years.
- It represented the first new drug for colorectal cancer in approximately 35 years.
Conclusions:
- Tomudex exemplifies successful drug development in antifolate therapy, overcoming previous solubility and toxicity issues.
- The drug's mechanism, utilizing the reduced-folate carrier (RFC) and folylpolyglutamate synthetase (FPGS), is crucial for its efficacy.
- The development of Tomudex underscores the importance of targeted drug design and collaborative research in oncology.