Resistance to purine analogs by loss of nucleotide-forming capacity was observed in a number of experimental tumor systems. Such resistance frequently was accompanied by loss of specific purine ribonucleotide pyrophosphorylase activities. However, it is evident that other mechanisms of resistance to purine analogs also exist both in mouse leukemia and in human leukemia.
Attention was focused on a locus of action of 6-mercaptopurine, as the ribonucleotide, at an early step on the purine biosynthetic pathway—namely, the site of end-product inhibition by purine ribonucleotides. In a human neoplasm grown in cell culture, 6-mercaptopurine was a potent inhibitor of this early step in purine biosynthesis, in agreement with work in mouse neoplasms.
The experimental work described was supported by the Cancer Chemotherapy National Service Center, National Cancer Institute, NIH (Contract No. SA-43-ph-2433), and by grants from the Charles F. Kettering Foundation and the Alfred P. Sloan Foundation.