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Metabolic Effects of 6-Thioguanine

I. Studies on Thioguanine-resistant and -sensitive Ehrlich Ascites Cells^*

Alan C. Sartorelli, G. A. LePage and E. C. Moore

( McArdle Memorial Laboratory, Medical School, University of Wisconsin, Madison 6, Wis.)

A subline of the Ehrlich ascites carcinoma exhibiting resistance to thioguanine was developed by consecutive passage of cells in mice treated with doses of 6-thioguanine. The change was found to be stable and heritable.

Cross-resistance to 6-mercaptopurine was demonstrated, while sensitivity to A-methopterin and azaserine was retained.

Both the derived thioguanine-resistant cells and two naturally thioguanine-resistant neoplasms were capable of metabolizing the antimetabolite to the nucleotide level.

The thioguanine-resistant population was slightly more susceptible to combination therapy of azaserine plus thioguanine than the parent thioguanine-sensitive tumor. Azaserine pretreatment not only increased the quantity of thioguanine nucleotides formed but also increased the quantity of thioguanine found in the nucleic acid fraction of the resistant Ehrlich ascites cells. These effects appear to explain in part the sensitivity of thioguanine-resistant cells to combination therapy with azaserine and thioguanine.

The presence of more active degradative enzymes for thioguanine appeared to be the biochemical basis for resistance to this drug in the thioguanine-resistant subline of the Ehrlich carcinoma.

^* This research was supported in part by United States Public Health Service Grant No. C2491 and in part by the Alexander and Margaret Stewart Fund.

Present address: The Samuel Roberts Noble Foundation, Inc., Biomedical Division, Ardmore, Oklahoma.

Present address: Department of Biological Sciences, Stanford Research Institute, Menlo Park, California.

Present address: Department of Biochemistry, University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston 25, Texas.

Received 7/ 2/58.