39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 519 



enzymic reactions of this analog at the nucleotide level; therefore, an evaluation of 

 its mechanism of action as an inhibitor of growth must await further investigation. 

 It is of interest, however, that thiouracil inhibited the catabolic release of carbon 

 dioxide-C 14 from uracil-2-C 14 in rats previously treated with acetylaminofluorene to 

 induce a "preneoplastic" state in the liver. 519 Although the analog was incorporated 

 into nucleic acids, it did not prevent the incorporation of uracil. 520 Furthermore, this 

 analog suppressed the induction of hepatomas in rats by acetylaminofluorene, an 

 effect which could be overcome by uracil without suppressing the hyperplasia of the 

 thyroid caused by thiouracil. 514 The metabolic alteration of thiouracil in rats results 

 in the formation of minor amounts of 2-methylthiouracil and inorganic sulfate. 522 



VI. Other Agents Which Influence Nucleic Acid Metabolism 



1. Urethane 



This chemically simple substance, ethyl carbamate (C 2 H 5 — CO — NH 2 ), 

 although known as a narcotic agent since 1885, was not recognized until 

 relatively recent years as having the capacity to affect cellular reproduction 

 and nucleic acid metabolism. As a result of studies which showed that ure- 

 thane produced arrest of mitosis in certain plants, the compound received 

 attention as an inhibitor of the growth of various transplantable neo- 

 plasms, 468, 523 and also of spontaneous leukemias in mice. 524 It is used to a 

 limited extent in the therapy of certain neoplastic states in man, particu- 

 larly myelogenous leukemia and multiple myeloma. 525527 Urethane has also 

 been shown to induce neoplasms in certain strains of mice and rats, particu- 

 larly adenomas of the lungs, 528-530 but also tumors of the liver, stomach, 

 skin, and other tissues, 529 " 531 and to augment, in mice, the leukemogenic ac- 

 tivity of X-rays, estrogenic hormones, and methylcholanthrene. 531 Exten- 

 sive study of the relationship between structure and biological activity has 

 shown that the oncogenic and antileukemic actions in mice of compounds 

 related to urethane are remarkably specific, since even the smallest struc- 

 tural alterations abolish or greatly reduce activity. 532 " 535 Nevertheless, the 



522 E. J. Sarcione and J. E. Sokal, J. Biol. Chem. 231, 605 (1958). 



523 A. Haddow and W. A. Sexton, Xature 157, 500 (1956). 



524 L. W. Law, Proc. Xatl. Acad. Sci. U. S. 33, 204 (1947). 



625 E. Paterson, A. Haddow, I. ApThomas, and J. M. Watkinson, Lancet i, 677 (1946). 



626 L. Berman and A. R. Axelrod, Am. J. Clin. Pathol. 18, 104 (1948). 



527 J. P. Loge and R. W. Rundles, Blood 4, 201 (1949). 



528 A. Nettleship and P. S. Henshaw, J. Xatl. Cancer Inst. 4, 309 (1943). 



529 W. G. Jaffe\ Cancer Research 7, 107 (1947). 



530 S. Rogers, J. Exptl. Med. 105, 279 (1957). 



531 S. Kawamoto, X. Ida, A. Kirschbaum, and G. Taylor, Cancer Research 18, 725 

 (1958). 



532 C. D. Larsen, J. Xatl. Cancer Inst. 8, 99 (1947); 9, 35 (1948). 



533 H. E. Skipper, C. E. Bryan, W. H. Riser, Jr., M. Welty, and A. Stelzenmuller, 

 ./. Natl. Cancer Inst. 9, 77 (1948). 



534 H. E. Skipper and C. E. Bryan, J. Xatl. Cancer Inst. 9, 391 (1948). 



