Increase of phosphoribosylpyrophosphate levels in cultured L1210 leukemia cells exposed to methotrexate.

Abstract

MTX‡ is a folic acid analog that binds to the enzyme dihydro-folate reductase and inhibits its activity depleting the cells of reduced folates. It blocks the synthesis of dTMP from dUMP and de novo purine biosynthesis by decreasing the availability of reduced folates1. MTX effects on cell metabolism can be reversed not only by folinic acid (5-formyltetrahydrofolic acid) but also by either TdR alone or TdR plus a purine base or nucleoside2–6 which provide for nucleotide synthesis through salvage pathways. Purine bases are converted to nucleotides by phosphoribosyltransferases in the presence of PRPP as the phosphoribosyl donor and TdR phosphorylation to dTMP by TdR kinase requires ATP. MTX has been demonstrated to cause a rapid decrease of intracellular ATP levels, which could restrict the cellular utilization of TdR7 . The purpose of our study was to evaluate the effect of MTX on the intracellular levels of PRPP in order to assess the availability of PRPP for purine salvage during MTX treatment.KeywordsFolinic AcidPurine BaseEhrlich Ascites Carcinoma CellPurine BiosynthesisL12l0 CellThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.