SOME METABOLIC EFFECTS EXERTED BY AZASERINE AND PURINE ANALOGS IN VIVO.

Summary The biochemical mechanisms involved in the synergistic anti-neoplastic activity of combinations of azaserine and certain purine analogs was studied in a subline of Sarcoma 180 that neither was inhibited by purine analogs alone nor responded in a synergic manner to their combinations with azaserine. 6-Chloropurine, 6-thioguanine, 6-mercaptopurine, and their ribonucleosides inhibited the incorporation of glycine-2-C 14 into nucleic acid guanine of Sarcoma 180; in addition, the purinethiols decreased the incorporation of glycine into nucleic acid adenine of this neoplasm. In the purine analog-resistant neoplasm (Sarcoma 180/TG), the analogs did not decrease the utilization of isotopic glycine for the biosynthesis of guanine nucleotides; however, 6-thioguanine and 6-thioguanosine both inhibited the formation of adenine nucleotides de novo . Azaserine markedly depressed the synthesis of purine nucleotides de novo in both tumors. 6-Thioguanine and its ribonucleoside decreased the conversion of both hypoxanthine-8-C 14 and guanine-8-C 14 to nucleic acid purines in both cell lines. Thioguanine mononucleotide was formed from thioguanine by both tumors; however, considerably more thioguanine nucleotide was present in the sensitive cells than in the resistant ones. This difference appeared to be attributable to a greater capacity of Sarcoma 180 to maintain an intracellular concentration of analog nucleotide. Pretreatment with azaserine caused an increase in the quantity of acid-soluble thioguanine nucleotide, as well as an increase in the amount of 6-thioguanine associated with the nucleic acids in both neoplasms.