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Decreased Feedback Inhibition in a 6-(Methylmercapto)purine Ribonucleoside-resistant Tumor¹

University of Alberta Cancer Research Unit (McEachern Laboratory) and Department of Biochemistry, Edmonton, Alberta, Canada

Some biochemical effects of 6-(methylmercapto)purine ribonucleoside (Me6MPR) have been compared in cells of the Ehrlich ascites carcinoma and of a Me6MPR-resistant subline. The sole metabolite of Me6MPR in both cell types was Me6MPR-5'-phosphate, and both formed the nucleotide at the same rate. This metabolite persisted for longer periods in the sensitive cells than in the resistant cells.

Me6MPR and guanine were less effective as feedback inhibitors of purine biosynthesis de novo in drug-resistant cells than in cells of the sensitive parent tumor, whereas adenine was equally effective in either. The phosphoribosylpyrophosphate amidotransferase activity of resistant cells was inhibited less than that of sensitive tumor cells. These results are consistent with the conclusion that the Me6MPR-resistant cells possess an altered amidotransferase which binds Me6MPR-5'-phosphate less well, or for which such binding has less inhibitory effect than for the enzyme in sensitive cells.

¹ This work was supported by the Medical Research Council and the National Cancer Institute of Canada.

Received 2/ 6/67. Accepted 5/23/67.