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Mechanism of the Growth Inhibition Potentiation Arising from Combination of 6-Mercaptopurine with 6-(Methylmercapto)purine Ribonucleoside¹

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

The antitumor effects of 6-mercaptopurine (6MP) and 6-(methylmercapto)purine ribonucleoside (Me6MPR) are distinctly potentiated when these agents are used together in the treatment of certain mouse tumors, including the Ehrlich ascites carcinoma. This paper is concerned with the biochemical mechanism of this potentiation.

Prior treatment of Ehrlich ascites carcinoma cells with Me6MPR enhanced several fold their ability to convert 6MP to 6MP ribonucleotide (thioinosinate) and their content of 5-phosphoribosyl-1-pyrophosphate. These related effects were demonstrable 96 hr after a single Me6MPR treatment and were evidently due to the presence in the tumor cells of methylthioinosinate, which had a half-life in excess of 96 hr. Both effects were absent when tumor cells were treated with Me6MPR plus adenine.

The inhibition of Ehrlich ascites carcinoma cell proliferation in vivo by single 6MP-Me6MPR treatments was distinctly increased if the Me6MPR component was given prior to 6MP. This result and the coincident changes in 6MP and 5-phosphoribosyl-1-pyrophosphate metabolism indicate that the Me6MPR-induced stimulation of 6MP anabolism is an important factor in the 6MP-Me6MPR therapeutic potentiation.

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

² Present address: Department of Experimental Therapeutics Roswell Park Memorial Institute, Buffalo, N. Y. 14203.

Received 6/11/69. Accepted 5/15/70.