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Trimetrexate: a second generation folate antagonist in clinical trial
1Department of Medicine, Yale University School of Medicine, New Haven, CT.
Summary
Trimetrexate, an antifolate drug, shows promise in cancer and infections like Pneumocystis pneumonia. It is effective against methotrexate-resistant tumors and has manageable side effects in clinical trials.
Area of Science:
- Pharmacology
- Oncology
- Infectious Diseases
Background:
- Trimetrexate is a lipophilic antifolate with antitumor and antimicrobial properties.
- It exhibits different transport and intracellular retention compared to methotrexate.
- This may offer advantages against methotrexate-resistant cancers due to transport or polyglutamylation differences.
Purpose of the Study:
- To evaluate the antitumor and antimicrobial activity of trimetrexate.
- To assess its efficacy and toxicity in clinical trials.
- To explore its potential use in methotrexate-resistant tumors and Pneumocystis pneumonia.
Main Methods:
- Preclinical studies assessing spectrum of activity and synergy with other agents.
- Phase II clinical trials evaluating efficacy against various cancers.
- Clinical trials assessing safety and efficacy in AIDS patients with Pneumocystis pneumonia, with leucovorin rescue.
Main Results:
- Demonstrated broader antitumor activity than methotrexate in preclinical studies.
- Showed synergistic antitumor activity when combined with other agents.
- Phase II trials indicate activity against breast, non-small-cell lung, and head and neck tumors.
- Effective treatment for Pneumocystis pneumonia in AIDS patients with leucovorin rescue, showing minimal toxicity.
Conclusions:
- Trimetrexate is a promising agent with significant antitumor and antimicrobial activity.
- It may be effective against methotrexate-resistant cancers.
- Its primary toxicity is hematologic with rapid recovery, and it shows promise for Pneumocystis pneumonia treatment in AIDS patients.