Human thymidylate synthetase—III

Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs?

“…Glutamates can be removed by γ -glutamyl hydrolase (GGH) and MTX monoglutamate is rapidly effluxed from the cell via membrane transporters of the ATP-binding cassette (ABC) family [222], especially ABCC1-4 and ABCG2 [223,224]. Inside the cell, MTX PG exert their anti-inflammatory actions through inhibition of essential enzymes of the folate pathway: dihydrofolate reductase (DHFR) [225], blocking the conversion of dihydrofolate (DHF) to tetrahydrofolate (THF) and ultimately leading to depletion of methionine and decreased DNA methylation; thymidylate synthase (TYMS) [226,227], interfering with de novo pyrimidine synthesis; and 5-aminoimidazole-4-carbox-amide ribonucleotide (AICAR) transformylase (ATIC) [148,228], an enzyme of the de novo purine synthesis, causing accumulation of AICAR, which will finally result in increased secretion of adenosine, a strong anti-inflammatory mediator [229,230]. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is not directly inhibited by MTX, but is affected by it because of its action in the folate pathway [176].…”

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

“…In the cell, MTX is metabolized to active polyglutamates, which are responsible for the disruption of the folate metabolic pathway by inhibiting enzymes that are essential for the DNA (Chabner et al, 1985). These include thymidylate synthase (TS; Szeto et al, 1979) and dihydrofolate reductase (DHFR; Galivan, 1980). Another key enzyme in the folate pathways is methylenetetrahydrofolate reductase (MTHFR), which produces 5-methyl-tetrahydrofolate (THF) from 5,10-methylene-THF, a major intermediary that is in turn synthesized by serine hydroxymethyltransferase (SHMT1).…”

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines

“…A lower requirement for polyglutamation may partially explain the good activity of MTX and aminopterin in the resistant cells (MTX is poorly polyglutamated at low intracellular concentrations). Furthermore, the polyglutamates of DHFR inhibitors, unlike the quinazoline TS inhibitors, are not significantly more potent as inhibitors of their target enzyme (Szeto et al, 1979;Chabner et al, 1985) than the parent monoglutamate, and the importance of their formation lies in their drug retentive properties (Galivan, 1980;Jolivet and Chabner, 1983). Thus, under continuous drug exposure conditions, the lack of polyglutamate formation is not particularly deleterious, however under short exposure conditions (6 h), when drug retention is important, MTX was -15-fold less active in the resistant than in the L1210 parental line.…”