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Molecular basis of antifolate resistance
1The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 32000, Israel. assaraf@tx.technion.ac.il
Cancer Metastasis Reviews
|March 3, 2007
Summary
Anticancer drug resistance to antifolates, crucial for DNA synthesis, arises from altered transporters and enzymes. Understanding these mechanisms, including ABC transporters, is key to developing new antifolate therapies and overcoming resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Folates are essential for one-carbon metabolism, vital for DNA synthesis.
- Antifolates like methotrexate target folate-dependent enzymes (e.g., DHFR) to inhibit cancer cell proliferation.
- Novel antifolates target enzymes such as thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTF).
Purpose of the Study:
- To review molecular mechanisms of antifolate resistance in cancer.
- To discuss emerging strategies for overcoming antifolate resistance.
- To highlight the role of transporter proteins in antifolate drug action and resistance.
Main Methods:
- Review of pre-clinical and clinical studies on antifolate resistance.
- Analysis of molecular alterations in folate transport and metabolism.
- Investigation of ATP-binding cassette (ABC) transporters in antifolate efflux.
Main Results:
- Antifolate resistance is linked to altered influx/efflux transporters (e.g., RFC) and target enzymes (DHFR, TS, FPGS).
- Overexpression of ABC transporters (MRP/ABCC, BCRP/ABCG2) actively extrudes antifolates, conferring resistance.
- Down-regulation of ABC transporters can increase intracellular folate pools, also leading to resistance.
Conclusions:
- Molecular characterization of antifolate resistance mechanisms is crucial for developing novel antifolates.
- Understanding transporter roles (RFC, ABCs) is vital for predicting and overcoming drug resistance.
- Future strategies should focus on rationally designed antifolates to circumvent resistance pathways.
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