Metabolic effects of 6-thioguanine. I. Studies on thioguanine-resistant and-sensitive Ehrlich ascites cells.

The guanine analog, 6-thioguanine (4), has been found to be a potent inhibitor of animal neoplasms (2) and human leukemia (5) when administered alone, and even more potent when used in com bination with the inhibitor of de novo purine syn thesis, azaserine (10, 12). We have developed a thioguanine-resistant subline of the Ehrlich ascites carcinoma. Using this as a tool, we have studied the metabolism of thioguanine in both the sensitive and resistant ascites cells and have obtained results which appear to explain the biochemical basis of resistance to this agent manifested by the derived resistant line of ascites cells. A preliminary report of these findings has been given (11). The data obtained in these experiments indi cate that both natural and derived thioguanineresistant neoplasms are capable of metabolizing the drug to the nucleotide form. Moreover, less total thioguanine was found in derived resistant cells than in the parent, sensitive tumor at all time periods assayed. This appears to be the re sult of more active thioguanine degradation in the resistant ascites cells. Studies on the relative susceptibility of the thioguanine-sensitive and -resistant ascites cells to combination therapy with azaserine plus thio guanine indicate that the resistant tumor line was slightly more susceptible to this drug combination.