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Biochemical Mechanisms for the Synergism between 6-Thioguanine and 6-(Methylmercapto)purine Ribonucleoside in Sarcoma 180 Cells¹

Section of Biochemical Pharmacology, Division of Biological and Medical Sciences, Brown University, Providence, Rhode Island 02912

The synergism between 6-(methylmercapto)purine ribonucleoside (MMPR) and 6-thioguanine was studied in the mouse Sarcoma 180 ascites tumor. The 5'-monophosphate nucleotide of MMPR forms rapidly to levels of 1 to 2 mM in the tumor cells, and the steady-state levels of 5-phosphoribosyl 1-pyrophosphate increase 4- to 5-fold in 6 to 12 hr. This permits a significantly greater synthesis of 6-thioguanosine monophosphate (6-thioGMP) after injection of 6-thioguanine. These findings are similar to those in previous reports concerning the synergism between 6-mercaptopurine and MMPR. In addition, MMPR increases the biological t_1/2 of 6-thioGMP from about 7 hr to 10 hr. The concentrations of ATP and GTP decrease by 50% or greater after MMPR and the concentration of UTP in the cell doubles, probably as the result of greater 5-phosphoribosyl 1-pyrophosphate availability for pyrimidine biosynthesis. With a 6-thioguanine-resistant cell line, the t_1/2 of 6-thioGMP is only 3 hr but increases to about 7 hr after MMPR pretreatment. Azaserine produces effects on endogenous nucleotide pools and 6-thioGMP formation similar to those of MMPR, but it is without effect on the t_1/2 of 6-thioGMP. The synergism between MMPR and other thiopurines may involve effects of MMPR on catabolism as well as synthesis of the analog nucleotides and sequential blockade of purine biosynthesis.

¹ This work was supported by USPHS Grant GM 16538 and Grant 07340 of the National Cancer Institute of the USPHS.

² Present address: Biochemistry Research, Southern Research Institute, Birmingham, Ala. 35205.

Received 3/30/72. Accepted 6/ 8/72.

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