Purine modulation of methotrexate cytotoxicity in mammalian cell lines

The modulation of MTX cytotoxicity by purines has been studied in a number of mammalian cell lines. In each case, it was found that exogenous purines (guanosine, deoxyguanosine, adenosine, deoxyadenosine, and hypoxanthine) both reduced and potentiated MTX cytotoxicity depending on the MTX concentration. At low MTX concentrations (less than 6 X 10(-8) M), purines reduced MTX toxicity and at higher concentrations they potentiated MTX toxicity. The reduction of low-concentration MTX cytotoxicity by purines was associated with the reversal of MTX-induced changes in deoxyribonucleotide pools. On the other hand, potentiation of MTX toxicity by purines was associated with substantial increases in deoxyadenosine 5'-triphosphate levels in conjunction with low deoxythymidine 5'-triphosphate levels. The magnitude of increase in deoxyadenosine 5'-triphosphate levels tended to correlate with the degree of potentiation which varied between 5-fold and 200-fold, depending on cell type and the exogenous purine.