486 R. E. HANDSCHUMACHER AND A. D. WELCH 



stimulation of the uptake of adenine seen in animals treated with azaserine; 

 however, with thioguanine the result is additional injury to the cell and the 

 potentiation of its antitumor activity by azaserine. 223 ' 224 



Studies on the metabolism of thioguanine by the bone marrow of guinea 

 pigs were conducted in an attempt to reveal the biochemical reason for the 

 primary sensitivity of this organ 222 ; however, a pattern not unlike that seen 

 with intestine was obtained. It was proposed, however, that bone marrow, 

 which is remarkably dependent upon preformed purines, 225, 226 would have 

 a higher sensitivity to an antagonist of preformed purines than would tissues 

 (such as intestine) which are capable of extensive synthesis de novo. Other 

 studies, 224 in which a thioguanine-resistant subline of the Ehrlich ascites 

 carcinoma was used, appear to substantiate the suggestion that formation of 

 the ribonucleoside or its phosphorylated derivatives is essential for tumor 

 inhibition. Extracts of sensitive and resistant tumors obtained at various 

 time periods after injection of thioguanine revealed a lower uptake and a 

 more rapid clearance of thioguanine from the resistant cells. Furthermore, 

 the anabolic conversion to thioguanylic acid was more extensive in the sen- 

 sitive cells, while the resistant cell line appeared to possess a more active 

 degradative system, giving rise to thioxanthine and thiouric acid; however, 

 the more extensive degradation by the resistant cells might be a reflection 

 of the inefficient conversion to thioguanylic acid. Another manifestation of 

 the difference between sensitive and resistant cells was found in the incor- 

 poration of thioguanine into the combined nucleic acids. Although less than 

 1 % of the nucleic acid purines of the sensitive cells was replaced by the 

 analog, little if any intact analog appeared in the nucleic acids of the resist- 

 ant cells. 227 As with mercaptopurine, a small amount of thioguanine was 

 converted in the mouse to acid-soluble and nucleic acid adenine and guanine, 

 a conversion which also was reduced in the resistant-cell line. 



Information concerning the primary site or sites of action of thioguanine 

 is not yet complete, but certain areas are indicated at this time. Preliminary 

 microbial reversal studies implied a blockade in the utilization of preformed 

 purines. However, in mammalian systems there may be several mechanisms 

 of action. 228 In mice bearing Ehrlich ascites carcinoma cells, the intraperi- 

 toneal injection of thioguanine, followed by injections of guanine-8-C 14 at 

 various time intervals, resulted in an inhibition of incorporation of the 

 guanine into RNA and DNA of the tumor cells to the extent of from 60 

 to 80% of that occurring in untreated animals. However, the inhibition 



223 A. C. Sartorelli and G. A. LePage, Cancer Research 18, 938 (1958). 



224 A. C. Sartorelli, G. A. LePage, and E. C. Moore, Cancer Research 18, 1232 (1958). 



225 R. A. Abrams and M. Bentley, Arch. Biochem. Biophys. 58, 109 (1955). 



226 L. G. Lajtha and J. R. Vane, Nature 182, 191 (1958). 



227 G. A. LePage, Proc. Am. Assoc. Cancer Research 3, 36 (1959). 



228 A. C. Sartorelli and G. A. LePage, Cancer Research 18, 1329 (1958). 



