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

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 4to 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 f1/2 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 t1/2 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 r1/2 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.