39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 513 



profound in the latter case. 462 The inhibitory effects of the analog on growth 

 could be prevented by uracil or cytosine, while orotic acid was relatively 

 ineffective in this respect. 46 '- 463 A number of workers have demonstrated 

 the inhibitory action of this compound on the growth of experimental 

 tumors. 464 " 468 Results obtained in the combination treatment of adenocar- 

 cinoma-755 with urethane and azauracil were particularly impressive. 468 



Further studies in microbial systems revealed extensive conversion of 

 azauracil to the ribonucleoside and the corresponding 5'-phosphates both 

 in S. faecalis and in E. cofo'. 469 ~ 473 To permit further study of these deriva- 

 tives a chemical synthesis of the ribonucleoside was devised, 469, m but 

 this has been replaced by a more efficient microbial formation, using E. 

 coli. i70 ' m Although such anabolic conversion is extensive in several bac- 

 terial strains, mammalian cells are relatively inefficient in this respect 467 ' 

 474, 475 anc j^ m addition, catabolize the analog (at least to a small extent) 

 to the following urinary products: glyoxylic acid semicarbazone, oxalic 

 acid, carbon dioxide, and an unidentified acid. 474 The biological properties 

 of the ribonucleoside, azauridine, are similar to those of azauracil except 

 that it is approximately 20 times more potent as an inhibitor of tumor 

 growth, 467 ' 476 is cleaved to a very minor degree even after oral adminis- 

 tration, 467 ' 474 ' 477 and is rapidly converted in the tissues tested to the 5'-phos- 

 phate. 477 " 480 In a strain of S. faecalis selected for resistance to azauracil, 



462 R. E. Handschumacher and A. D. Welch, Cancer Research 16, 965 (1956). 



463 J. Skoda and F. Sorm, Chem. listy 50, 1165 (1956) ; F. Sorm and J. Skoda, Collection 

 Czechoslov. Chem. Communs. 21, 487 (1956). 



464 M. T. Hakala, L. W. Law, and A. D. Welch, Proc. Am. Assoc. Cancer Research 2, 

 113 (1956). 



465 F. Sorm, A. Jakubovic, and L. Slechta, Experientia 12, 271 (1956). 



466 J. Sablik and F. Sorm, Neoplasm 4, 113 (1957). 



467 J. J. Jaffe, R. E. Handschumacher, and A. D. Welch, Yale J . Biol, and Med. 30, 

 168 (1957). 



468 G. B. Elion, S. Bieber, H. C. Nathan, and G. H. Hitchings, Cancer Research 18, 

 802 (1958). 



469 R. E. Handschumacher, Federation Proc. 16, 191 (1957). 



470 J. Skoda, V. F. Hess, and F. Sorm, Collection Czechoslov. Chem. Communs. 22, 



1330 (1957); Experientia 13, 150 (1957). 



471 R. E. Handschumacher, Biochim. el Biophys. Acta 23, 428 (1957). 



472 R. E. Handschumacher, Nature 182, 1090 (1958). 



473 R. E. Handschumacher, J. Biol. Chem., in press. 



474 R. E. Handschumacher and R. J. Davis, Abstr. Meeting Am. Soc. Pharmacol. Exptl. 

 Therap., Ann Arbor, p. 17 (1958). 



475 R. Schindler and A. D. Welch, Biochem. Pharmacol. 1, 132 (1958). 



476 F. Sorm and H. Keilova, Experientia 14, 215 (1958). 



477 V. Habermann and F. Sorm, Collection Czechoslov. Chem. Communs. 23, 2201 

 (1958). 



478 C. A. Pasternak and R. E. Handschumacher, Proc. Am. Assoc. Cancer Research 

 2, 233 (1958). 



