DHFR and neoplasm: The anti-tumor role of methotrexate is exerted most potently by blocking dihydrofolate reductase (DHFR), while pemetrexed has a multi-targeting role, acting on three key folate metabolism enzymes: TYMS, DHFR, and glycinamide ribonucleotide formyltransferase (GART)8, 14, 15.