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Methotrexate resistant cells as targets for selective chemotherapy
Abstract:
Strategies that are selective for eradicating methotrexate resistant cells are described. These strategies have been developed based on knowledge of the mechanism of drug resistance encountered in experimental systems and in the clinic. Drug resistance to methotrexate in experimental tumors is commonly due to either gene amplification (dihydrofolate reductase) or to impaired transport of methotrexate. While no effective drugs or methods to prevent gene amplification have been described, the concept of developing "pro drugs", i.e. a drug that is selectively reduced by dihydrofolate reductase to an inhibitor of another critical folate enzyme (thymidylate synthase, methionine synthetase, folylpolyglutamate synthetase) remains worthwhile. Second generation antifolates such as trimetrexate which are effective vs methotrexate transport resistant cells have already been developed and are in clinical trial.
Insights
New strategies target methotrexate-resistant cancer cells by understanding drug resistance mechanisms. Research focuses on developing novel antifolates and prodrugs to overcome resistance, with some agents in clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Methotrexate resistance in cancer is a significant clinical challenge.
- Common resistance mechanisms include dihydrofolate reductase gene amplification and impaired drug transport.
- Existing strategies for overcoming resistance are limited.
Purpose of the Study:
- To describe strategies for eradicating methotrexate-resistant cells.
- To explore novel therapeutic approaches based on understanding resistance mechanisms.
- To evaluate the potential of prodrugs and second-generation antifolates.
Main Methods:
- Analysis of established mechanisms of methotrexate resistance in experimental and clinical settings.
- Conceptual development of prodrugs targeting critical folate enzymes.
- Evaluation of second-generation antifolates, such as trimetrexate, against resistant cell lines.
Main Results:
- Identified dihydrofolate reductase gene amplification and impaired transport as key resistance mechanisms.
- Proposed the development of prodrugs selectively activated by dihydrofolate reductase.
- Second-generation antifolates demonstrate efficacy against methotrexate transport-resistant cells.
Conclusions:
- Targeted strategies can overcome methotrexate resistance.
- Prodrug development offers a promising avenue for novel antifolate therapies.
- Second-generation antifolates like trimetrexate show clinical potential in treating resistant cancers.