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Trimetrexate: clinical development of a nonclassical antifolate.
P J O'Dwyer1, R J DeLap, S A King
1Investigational Drug Branch, National Cancer Institute, Bethesda, MD.
NCI Monographs : a Publication of the National Cancer Institute
|January 1, 1987
Summary
Trimetrexate, a dihydrofolate reductase inhibitor, shows promise against methotrexate-resistant tumors. Its unique properties may offer improved efficacy and therapeutic index, though myelosuppression is a key toxicity to manage.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Trimetrexate is a novel antifolate agent targeting dihydrofolate reductase (DHFR).
- It exhibits cytotoxicity against tumors resistant to methotrexate.
- Its distinct physicochemical properties differentiate it from methotrexate, suggesting potential clinical advantages.
Purpose of the Study:
- To evaluate the efficacy and toxicity profile of trimetrexate.
- To explore the schedule-dependency of trimetrexate activity.
- To investigate its potential in treating methotrexate-resistant cancers.
Main Methods:
- Preclinical studies assessing in vitro and in vivo activity.
- Pharmacokinetic and pharmacodynamic evaluations.
- Phase I clinical trials to determine dose-limiting toxicities and maximum tolerated dose.
- Phase II studies initiating evaluation on a 5-day schedule.
Main Results:
- Trimetrexate demonstrates superior activity on repeated dose schedules in preclinical models.
- Myelosuppression emerged as the primary dose-limiting toxicity in Phase I human trials.
- The drug's lipophilicity and lack of reduced folate carrier transport are key characteristics.
Conclusions:
- Trimetrexate presents a promising therapeutic option for methotrexate-resistant malignancies.
- Schedule optimization is crucial for maximizing trimetrexate's efficacy and therapeutic index.
- Further clinical trials are warranted to establish its role in cancer treatment.