Methotrexate cytotoxicity: studies on its reversal by folates and nucleosides

The methotrexate (MTX) metabolite, 7-hydroxymethotrexate, which is potentially capable of influencing MTX rescue by affecting both MTX and reduced folate transport at the cell membrane, has been estimated in the plasma of patients receiving moderate doses (240 mg/m2) of MTX. Forty-eight hours after MTX dosage the level of 7-hydroxymethotrexate exceeded that of MTX by ten to one. Studies of the utilization of thymidine and inosine by MTX-treated L1210 cells in culture suggest that these cells may be able to utilize these substrates when their extracellular concentration is less than 1 microM. The incorporation of 14C hypoxanthine into the nucleotide pools and the nucleic acids of L1210 cells increases following exposure to MTX. This observation is compatible with the known increased availability of phosphoribosyl pyrophosphate in these cells following MTX treatment. These observations show ways in which naturally occurring nucleosides as well as metabolites of MTX itself may modulate the toxicity of the drug. Such observations may be relevant to the design of treatment and rescue protocols.