STUDIES ON MECHANISM OF AZASERINE-INDUCED DECREASE IN ACTIVITY OF THYMIDINE KINASE

The intraperitoneal injection of azaserine (O-diazoacetyl-l-scrine), a potent inhibitor of the synthesis of purine nucleotides de novo, into mice bearing sarcoma 180 ascites cells resulted in a decrease to about 25 per cent of normal in the activity of thymidine kinase of the neoplastic cells. Almost complete restoration of the activity of this enzyme was achieved by exposure in vivo of the azaserine-treated cells to a source of either preformed adenine or a mixture of thymidine and deoxycytidine. Treatment with azaserine caused a pronounced depletion of adenine nucleotide pools due to an inability of the drug-treated cells to synthesize purine nucleotides de novo. Provision to the cells of preformed adenine allowed circumvention of the metabolic blockade and adenine nucleotide pools were restored to normal, whereas the mixture of thymidine and deoxycytidine did not influence the size of the intracellular purine nucleotide pool in cells exposed to azaserine. The results are interpreted and discussed in terms of the role of the substrates in maintaining the intracellular concentration of thymidine kinase. © 1969.