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Use of Nucleosides in Resistance to 6-Thioguanine^*

( Life Sciences Research, Stanford Research Institute, Menlo Park, California)

Ascites cell tumors were found to cleave thioguanine riboside relatively rapidly. In tumor cell lines lacking the ribonucleotide pyrophosphorylase necessary for formation of thioguanine ribonucleotide, thioguanine riboside was converted to nucleotide to a small extent. This nucleotide formation was enhanced, after a short time lag, by 9-methyl thioguanine. The nucleoside, adenine arabinoside, was not cleaved by the tumor cells and inhibited the cleavage of thioguanine riboside. However, adenine arabinoside was rapidly metabolized so that its influence was brief. Inhibition of thioguanosine cleavage by 9-methyl thioguanine resulted in an increase in incorporation of thioguanine into RNA but not into DNA. Since this did not increase the survival time of mice bearing the ribonucleotide pyrophosphorylase-lacking tumors, the importance of achieving incorporation of thioguanine into DNA to obtain tumor inhibition would seem to have further support.

^* This work was supported in part by Contract No. SA-43-ph-3068 with the Cancer Chemotherapy National Servíce Center, National Cancer Institute, National Institutes of Health, and in part by a grant from the United States Public Health Service (CY-4551).

Received 12/10/62.