Potentiation by guanine nucleosides of the growth-inhibitory effects of adenosine analogs on L1210 and sarcoma 180 cells in culture.

ABSTRACT

The growth-inhibitory effect of 6-methylmercaptopurine riboside (MMPR) against leukemia L1210 cells in culture was dramatically potentiated by the addition of guanine nucleosides to the medium. In the presence of either deoxyguanosine or guanosine, the concentration of MMPR that caused 50% inhibition of growth was 35 times lower than in the absence of these nucleosides. Similar potentiation was also observed against Sarcoma 180 cells in culture by guanosine. The metabolic basis of this synergism was approached in a study of the incorporation of [14C]glycine into 5'-phosphoribosyl-N-formylglycinamide in Sarcoma 180 cells. The results show that the site of inhibition resulting in synergism is an early step in purine biosynthesis, probably phosphoribosyl pyrophosphate amidotransferase (EC 2.4.2.14). In the L1210 cell system, the addition of hypoxanthine to the medium prevented the potentiation of MMPR by guanine nucleosides supporting the conclusion that the site of the synergistic interaction involves purine biosynthesis de novo. While hypoxanthine partially reversed the growth-inhibitory effects of MMPR, an even higher degree of protection was observed in the presence of both uridine and hypoxanthine, suggesting that MMPR may have additional sites of action concerned with pyrimidine metabolism.