DHFR and metabolic disease: Tumors are not only genetic diseases but also metabolic disorders, as evidenced by the fact that even with ample oxygen supply, tumor cells prefer to undergo glycolysis, promoting lactic acid secretion, known as the “Warburg effect“.467 In 1948, Sidney Farber described how the anti-folate drug aminopterin inhibits dihydrofolate reductase, thereby blocking the synthesis of nucleic acids and proteins in acute leukemia in children.