The effects of methotrexate are not specific for cancer/neoplastic cells, and si

Question

The effects of methotrexate are not specific for cancer/neoplastic cells, and side effects of the drug are often experienced. These side effects include hair loss and low blood cell counts which are a result of methotrexate’s effect on processes with rapidly dividing cells. To alleviate some of the side effects, patients will often be given a dose of folinic acid. Folinic acid is a formyl derivative of tetrahydrofolic acid that can be used by normal cells without the action of dihydrofolate reductase. How does this folinic acid “rescue” act to alleviate/reduce the side effects?

Explanation / Answer

The enzyme dihydrofolate reductase (DHFR) reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is essential for biosynthesis of thymidine as well as certain amino-acids like methionine. Methotrexate inhibits DHFR competitively by binding the enzyme with typically 1000-fold greater affinity than folic acid. As a result, synthesis of tetrahydrofolate is stalled. The side-effects of methotrexate therapy are due to the deficiency of tetrahydrofolate in healthy cells.

Folinic acid, chemically 5-formyltetrahydrofolate, can directly convert to tetrahydrofolate, without the need for DHFR enzyme activity. Therefore, cells are able to synthesize tetrahydrofolate even while the DHFR is inhibited by methotrexate. Moreover, folinic acid is also known to allow to some extent the reactivation of DHFR inhibited by methotrexate. Cells, thus rescued by folinic acid of their inability to synthesize tetrahydrofolate, can continue to synthesize essential amounts of thymidine and amino-acids. This reduces and alleviates the side-effects of methotrexate.

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