Studies on the mechanism of action of 6-mercaptopurine in sensitive and resistant L1210 leukemia in vitro.

Abstract

Summary A study was made of the effects of 6-mercaptopurine (6-MP) upon nucleic acid metabolism in L1210 leukemia cells in vitro. Pharmacological concentrations of 6-MP inhibited the incorporation of both hypoxanthine and glycine into adenine nucleotides. Higher concentrations of 6-MP inhibited the incorporation of hypoxanthine into both adenine and guanine nucleotides. In a subline of L1210 which is resistant to 6-MP there was much less utilization of hypoxanthine than in the sensitive line, and incorporation into both adenine and guanine moieties was strongly inhibited by 6-MP. On the contrary, utilization of glycine for nucleotide purine synthesis was unaffected by 6-MP. These findings support the hypothesis that in L1210 leukemia 6-MP is metabolized to its ribotide, and this produces a metabolic block in the conversion of inosinic acid to adenylic acid. They further indicate that, in the L1210 cells resistant to 6-MP, there is a very limited capacity to convert 6-MP and hypoxanthine to ribotides. This leads to competition between 6-MP and hypoxanthine and to formation of insufficient 6-MP ribotide to cause the critical block.