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.


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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