A mechanism of resistance to 6-mercaptopurine: metabolism of hypoxanthine and 6-mercaptopurine by sensitive and resistant neoplasms.

Summary Leukemia L1210 ascites tumor cells sensitive to inhibition by 6-mercaptopurine were observed to metabolize hypoxanthine-8-C14 and 6-mercaptopurine-S35 to ribonucleotide derivatives in vivo. Hypoxanthine-8-C14 extensively labeled adenylic and guanylic acids of L1210 nucleic acids. Soluble enzyme preparations from L1210 ascites cells catalyzed the reactions of adenine, guanine, 8-azaguanine, hypoxanthine, and 6-mercaptopurine with 5-phosphoribosyl-1-pyrophosphate (PRPP) to yield 5′-ribonucleotide derivatives. Lines of L1210 resistant to 6-mercaptopurine failed to form significant amounts of inosinic acid or 6-mercaptopurine ribonucleotide in vivo. The nucleic acids of the drug-resistant leukemic cells exposed in vivo to hypoxanthine-8-C14 were not extensively labeled. Soluble enzyme preparations from the L1210 ascites cells resistant to purine antagonists did catalyze the reaction of adenine with PRPP to yield adenylic acid but did not yield significant amounts of the 5′-ribonucleotides of guanine, 8-azaguanine, hypoxanthine, or 6-mercaptopurine. These findings support the interrelated hypotheses that (a) the metabolism of 6-mercaptopurine to a ribonucleotide derivative constitutes a lethal synthesis and that (b) an effective mechanism of resistance to 6-mercaptopurine in L1210 mouse leukemia is a decrease in the enzymic capacity of the drug-resistant leukemic cells to form 6-mercaptopurine ribonucleotide.