Antifolates

Antifolates are a class of antimetabolite medications that inhibit the actions of folic acid (vitamin B9). These compounds interfere with the synthesis of nucleotides and nucleic acids, which are essential for DNA replication and cell division. Antifolates are primarily used in the treatment of cancer, bacterial infections, and certain autoimmune diseases.

Mechanism of Action

Antifolates work by inhibiting the enzyme dihydrofolate reductase (DHFR), which is crucial for the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is necessary for the synthesis of thymidylate, purines, and certain amino acids. By blocking this pathway, antifolates prevent the formation of DNA and RNA, leading to cell death, particularly in rapidly dividing cells such as cancer cells and bacteria.

Types of Antifolates

There are several types of antifolates, each with specific applications:

• Methotrexate - Used in the treatment of various cancers, including leukemia, lymphoma, and breast cancer. It is also used in the management of rheumatoid arthritis and psoriasis.
• Pemetrexed - Primarily used for the treatment of non-small cell lung cancer and mesothelioma.
• Trimethoprim - Commonly used in combination with sulfamethoxazole to treat urinary tract infections and other bacterial infections.
• Pyrimethamine - Used in the treatment of malaria and toxoplasmosis.

Clinical Uses

Antifolates are used in various clinical settings:

• Cancer Treatment - By inhibiting DNA synthesis, antifolates are effective in treating rapidly dividing cancer cells. They are often used in combination with other chemotherapeutic agents.
• Antibacterial Therapy - Trimethoprim and pyrimethamine are used to treat bacterial infections by inhibiting bacterial DHFR.
• Autoimmune Diseases - Methotrexate is used in low doses to manage autoimmune conditions such as rheumatoid arthritis and psoriasis by modulating the immune response.

Side Effects

The use of antifolates can lead to several side effects, primarily due to their impact on rapidly dividing cells. Common side effects include:

• Myelosuppression - Decreased production of blood cells, leading to anemia, leukopenia, and thrombocytopenia.
• Gastrointestinal toxicity - Nausea, vomiting, and mucositis.
• Hepatotoxicity - Liver damage, particularly with long-term use.
• Nephrotoxicity - Kidney damage, especially with high doses of methotrexate.

Resistance

Resistance to antifolates can develop through various mechanisms, including:

• Increased expression of DHFR.
• Mutations in the DHFR gene that reduce drug binding.
• Increased efflux of the drug from cells.

Conclusion

Antifolates are a critical class of drugs in the treatment of cancer, bacterial infections, and autoimmune diseases. Their ability to inhibit folic acid metabolism makes them effective in targeting rapidly dividing cells, although their use is associated with significant side effects and the potential for resistance.

See Also

• Antimetabolite
• Chemotherapy
• Folic acid
• Dihydrofolate reductase
• Cancer treatment
• Bacterial infection
• Autoimmune disease