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ICI D1694, an inhibitor of thymidylate synthase for clinical study
A L Jackman1, D I Jodrell, W Gibson
1Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
The TS inhibitor, ICI D1694, is a highly potent inhibitor of tumour growth in vitro and in vivo. Uptake via the RFC and rapid metabolism to polyglutamate forms appear to be responsible for potency. Antiproliferative toxicity in mice was evident although the dose-limiting renal toxicity experienced with CB3717 was not apparent.
Insights
The thymidylate synthase (TS) inhibitor ICI D1694 effectively inhibits tumor growth. Its potency is linked to cellular uptake via the reduced folate carrier (RFC) and rapid metabolism, with reduced renal toxicity compared to CB3717.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Thymidylate synthase (TS) is a critical enzyme in DNA synthesis.
- Novel TS inhibitors are sought for cancer therapy.
- ICI D1694 is a potent TS inhibitor.
Purpose of the Study:
- To evaluate the efficacy of ICI D1694 in inhibiting tumor growth.
- To investigate the mechanisms underlying ICI D1694's potency.
- To assess the toxicity profile of ICI D1694 in vivo.
Main Methods:
- In vitro and in vivo studies of tumor growth inhibition.
- Investigation of cellular uptake mechanisms (reduced folate carrier - RFC).
- Metabolism studies to identify polyglutamate forms.
- Toxicity assessment in mice, comparing with CB3717.
Main Results:
- ICI D1694 demonstrated high potency in inhibiting tumor growth both in vitro and in vivo.
- Uptake via RFC and rapid metabolism to polyglutamate forms were identified as key factors for its potency.
- Antiproliferative toxicity was observed in mice.
- The dose-limiting renal toxicity seen with CB3717 was not apparent with ICI D1694.
Conclusions:
- ICI D1694 is a highly potent TS inhibitor with promising anti-tumor activity.
- Its unique uptake and metabolism contribute to its efficacy.
- ICI D1694 exhibits a potentially favorable toxicity profile compared to existing agents like CB3717.