Inhibition of ascites cell growth by combinations of 6-thioguanine and azaserine.

Azaserine has been shown to be a potent in hibitor of de novo purine synthesis in both solid tumors (1, 13) and ascites cells (5, 6, 10). The duration of inhibition has been correlated with increases in the survival time of tumor-bearing hosts (7, 8). During inhibition of de novo purine synthesis by azaserine, the ascites cells maintain the ability to utilize preformed purines and pre sumably survive through use of this mechanism (9, 192). An attempt was made to find an agent which would inhibit the utilization of preformed purines, thus producing a concurrent blockage of two alternate pathways, when combined with azaserine. 6-Thioguanine (3), an inhibitor of both animal neoplasms (92) and human leukemia (4), was found to inhibit guanine-8-C'4 incorporation into nucleic acid guanine of Ehrlich ascites cells (11). Tarnowski and Stock (14) have reported that, among a number of combinations, that of aza serine and thioguanine was synergistic in inhibit ing the RC mammary carcinoma. No synergistic response was found when the mouse mammary carcinoma S-790 was used. In these experiments the two drugs were used in various combinations to determine the effects of concurrent inhibition of two alternate pathways of purine biosynthesis on a spectrum of ascites tumor cells. The combination of antimetabolites was exceptionally effective against the Ehrlich ascites carcinoma, the TA3 ascites carcinoma, and the Sarcoma 180 ascites. The Mecca lympho sarcoma in solid or ascites form and the 6C81[ED ascites were found to be relatively resistant.