Aminopterin

Aminopterin structural formula V2

Aminopterin is a chemotherapy drug and an antimetabolite of the folic acid (vitamin B9) pathway, which was used in the past for treating certain types of cancer. It functions by inhibiting dihydrofolate reductase (DHFR), an enzyme critical in the folic acid pathway, leading to a reduction in DNA synthesis and thus, cell replication. Aminopterin was one of the first drugs to demonstrate the effectiveness of targeted cancer therapy, paving the way for the development of other antimetabolites in cancer treatment.

History

Aminopterin was synthesized in the 1940s and was used in the late 1940s and 1950s for childhood leukemia treatment. Its use was largely replaced by methotrexate, a similar but less toxic compound. The historical significance of aminopterin lies in its role in the development of chemotherapy for cancer, as it was among the first substances to show that cancer could be treated by pharmacological agents.

Mechanism of Action

Aminopterin works by competitively inhibiting the enzyme dihydrofolate reductase (DHFR). DHFR is essential for the synthesis of tetrahydrofolate, a form of folic acid required for the synthesis of nucleotides. Nucleotides are the building blocks of DNA and RNA, so by inhibiting their synthesis, aminopterin effectively slows down or stops the proliferation of cancer cells, which are characterized by their rapid division and growth.

Clinical Use and Limitations

While aminopterin was a breakthrough in cancer treatment, its clinical use was limited due to its toxicity. Side effects, including severe nausea, vomiting, and myelosuppression (a decrease in bone marrow activity leading to reduced production of blood cells), were common, leading to the search for less toxic alternatives. Methotrexate, a drug with a similar mechanism of action but lower toxicity, eventually replaced aminopterin in most therapeutic applications.

Legacy

Despite its historical importance, aminopterin is no longer used therapeutically due to its side effects and the availability of safer alternatives. However, its development marked a significant milestone in the history of chemotherapy, demonstrating that chemical agents could effectively treat cancer. Research into the mechanisms of action and resistance to drugs like aminopterin has contributed to the broader understanding of cancer biology and the ongoing development of new therapeutic strategies.

See Also

• Chemotherapy
• Antimetabolite
• Folic acid
• Dihydrofolate reductase
• Methotrexate
• Cancer therapy