Dihydrofolate reductase pathway bypass

The Dihydrofolate reductase (DHFR) pathway bypass via reduced folate supply is a pharmacological mechanism used to circumvent the metabolic block created by DHFR inhibitors like methotrexate (StatPearls, 2023). DHFR is essential for regenerating tetrahydrofolate from dihydrofolate; its inhibition leads to a depletion of the reduced folate pool, halting DNA synthesis and causing cell death (NCBI, 2022). By providing exogenous reduced folates such as leucovorin (folinic acid), the cell can acquire the necessary folate cofactors without the need for functional DHFR activity (PubChem, 2024). This rescue mechanism is standard in high-dose methotrexate protocols to protect healthy tissues, such as the bone marrow and gastrointestinal epithelium, from lethal folate depletion (NCI, 2023). However, this bypass can also occur as a resistance mechanism in cancer cells if they upregulate folate transporters like SLC19A1 or if the microenvironment provides sufficient reduced folates (PubMed, PMID: 22138205). Proper timing of the bypass is critical to ensure that the therapeutic effect of the DHFR inhibitor is not neutralized in the target tumor cells (StatPearls, 2023).

Other names

Leucovorin rescueFolinic acid bypassReduced folate supplementationMethotrexate rescue5-formyltetrahydrofolate bypass

Provision of exogenous reduced folates (e.g., leucovorin) that enter the folate pool downstream of dihydrofolate reductase (DHFR), bypassing the enzymatic block and restoring nucleotide synthesis.