Author(s): JustinLawson and Edward A. Sausville
Folate (in the form of folic acid or tetrahydrofolate) is an essential nutrient recognized during the mid-20th century as a vitamin in the B complex (specifically vitamin B9). Deficiency of folate is associated with megaloblastic or macrocytic anemia. The biochemical basis for this was defined also in the mid-20th century as related to the necessity of reduced folate derivatives for the synthesis of nucleic acid precursors, including thymine nucleosides as well as the purine precursors, as well as participating other reactions in metabolism to move “one carbon” units critical to formation of certain amino acids in particular. Understand ing of this biochemistry actually suggests ways of interfering with folate metabolism in a way that should cause inhibition of malignant cell growth. Indeed, the use of certain antifolate agents such as methotrexate was historically associated with the first transient dramatic responses of pediatric acute leukemia to drug therapy and encouraged the development of further advances in chemotherapy so that now this disease is in the majority of cases a curable neoplasm. Likewise, single agent methotrexate led to the first cures of a solid tumor by chemotherapy in the case of choriocarcinoma.
Folic acid is an essential nutrient, which acts as a supplier of methyl groups to synthesize purines, pyrimidines, and certain amino acids. When able to donate methyl groups, folic acid exists as a reduced, methylene folate known as �201C;5,10-methylenetetrahydrofolate” (Me-THF).
At doses of ≤ 25 mg/m2, adequate MTX absorption may be achieved by oral doses. Higher doses require parenteral (IV or IM) for complete absorption. MTX, PMX, and PDX are all eliminated primarily via renal excretion predominantly by glomerular filtration and tubular secretion. IMPORTANT: Dose reduction required with renal dysfunction and administration may not be possible in renal failure. Interact with drugs affecting renal blood flow or tubular function (e.g., nonsteroidal anti-inflammatory agents, aspirin).
MTX binds to albumin within the blood and toxicity may be enhanced by other albumin binders (e.g., sulfonamides, phenytoin). High doses of MTX (>7,500 mg/m2) can affect liver function. This typically manifests as a transient elevation of liver enzymes that resolves within a few days, although this effect may persist in some patients. Long-term exposure to low doses of MTX can also lead to liver damage.
Tumor cells may also have altered polyglutamylation and cellular transport mechanisms compared to normal cells. When administered at doses >500 mg/m2, MTX can enter cells by passive diffusion, not requiring folate cell membrane transport; this strategy is used in treatment of sarcomas, lymphomas, and ALL.
Antifolates are a subclass of antimetabolites that cause their cytotoxic effects by preventing the de novo formation of precursors of nucleic acid synthesis, especially thymidine, a nucleic acid essential for the creation of new DNA. The mechanisms vary depending on the drug, but primarily include inhibition of de novo synthesis of thymidine monophosphate (dTMP) from uridine monophosphate (dUMP). As these medications prevent the synthesis of DNA, they are active during the S phase of the cell cycle. Toxicity of antifolates may be mitigated by rescue strategies with folic acid analog leucovorin, avoidance of drugs that interact with drug elimination processes, and in the case of methotrexate administration under the correct clinical contexts, of a recombinant drug metabolizing enzyme.