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



ability of urethane to initiate pulmonary adenomas in mice appears to be 

 caused by a metabolite of the compound 530, 536 or, perhaps less likely, by a 

 substance released from the tissues of animals given even a single injection 

 of urethane. 



The nature of the oncogenic substance presumably derived from urethane 

 is unknown, but the parent compound, separately labeled with C 14 in its 

 alkyl or carbonyl groups, is metabolized rapidly, apparently largely to etha- 

 nol, carbon dioxide, and ammonia. 537 " 539 Studies with the sperm of the sea 

 urchin have indicated that carbon derived from either the carbonyl or the 

 methylene groups of urethane is fixed to nuclear material, 540 while studies 

 with mice showed that, although total uptake was greatest in the nuclear 

 fraction of lung tissue, the highest concentration of C 14 per milligram of pro- 

 tein occurred in the pulmonary mitochondria. 539 In view of the rapid catabo- 

 lism of urethane, the significance of these uptakes of radioactive carbon 

 cannot be evaluated. 



Recent study of a large number of derivatives of urethane as initiators of 

 lung adenomas and neoplasms of the skin in mice disclosed no substances 

 more active than the parent compound. 535 The modifications in structure 

 of urethane involved changes in the carbamyl and carboethoxy portions, 

 phosphorylated derivatives, and addition compounds with keto acids (for 

 the effect of oxaloacetate, see below) and amino acids. Although less active 

 than urethane, iV-hydroxyurethane exhibited the most marked activity in 

 inducing lung tumors, while carboethoxyphosphate also appeared to have 

 some activity. 



Investigation 468 of the growth of adenocarcinoma-755 in C57BL mice 

 showed that the inhibitory activity of azauracil could be potentiated strik- 

 ingly by urethane, but this result could not be obtained with other experi- 

 mental neoplasms. 541 On the other hand, the remarkable sensitivity of this 

 tumor system to inhibition by azacytosine was but little affected by the 

 concurrent administration of urethane. 468 



Important studies 530 ' 536, 542 - 544 of the oncogenic action of urethane in 



635 I. Berenblum, D. Ben-Ishai, N.Haran-Ghera, A. Lapidot, E. Simon, and N. 



Trainin, Biochem. Pharmacol. 2, 168 (1959). 

 536 S. Rogers, J. Natl. Cancer Inst. 15, 1675 (1955). 

 637 J. H. Mitchell, Jr., (). S. Hutchison, H. E. Skipper, and C. E. Bryan, J. Biol. 



Chem. 180, 675 (1949). 



538 H. E. Skipper, L. L. Bennett, Jr., C. E. Bryan, L. White, Jr., M. A. Newton, and 

 L. Simpson, Cancer Research 11, 46 (1951). 



539 I. Berenblum, N. Haran-Ghera, R. Winnick, and T. Winnick, Cancer Research 18, 

 181 (1958). 



540 I. Cornman, H. E. Skipper, and J. H. Mitchell, Jr., Cancer Research 11, 195 (1951). 

 841 G. B. Elion, Personal communication (1959). 



542 S. Rogers, J. Exptl. Med. 93, 427 (1951). 



643 S. Rogers, J. Natl. Cancer Inst. 15, 1675 (1955). 



