The observed effects of 6-mercaptopurine on purine synthesis de novo can be attributed to inhibition by 6-mercaptopurine ribonucleotide of phosphoribosylamine synthesis. Azaserine-induced accumulation of formylglycinamide ribonucleotide (FGAR) in human tumor cells in culture was inhibited by low concentrations of 6-mercaptopurine and 6-thioguanine; such inhibition of FGAR accumulation did not occur in a mercaptopurine-resistant subline that lacked inosinic and guanylic acid pyrophosphorylase activities, the enzyme system by which 6-mercaptopurine ribonucleotide and 6-thioguanylic acid are formed. Resistance to mercaptopurine has been seen to be accompanied frequently by decrease or loss of these enzyme activities. Such loss of enzyme activity appears to be a genetically stable and heritable characteristic of resistant cells. Resistance to mercaptopurine by means other than loss of capacity for ribonucleotide formation is also evident.

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The experimental work reported herein was supported by the Cancer Institute, under the National Institutes of Health Contract No. SA-43-ph-2433, and by grants from the Charles F. Kettering Foundation and the Alfred P. Sloan Foundation.

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