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Studies on the Mechanism of Action of 6-Mercaptopurine in Sensitive and Resistant L1210 Leukemia In vitro^*

( Clinical Pharmacology and Experimental Therapeutics Service, National Cancer Institute, Bethesda, Md.)

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.

^* Presented in part before the 50th annual meeting of the American Association for Cancer Research, April, 1959, Atlantic City, N.J., and published in abstract form in the scientific Proceedings of that meeting.

Received 8/ 3/59.