39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 521 



mice have shown convincingly that injection of the agent (e.g., a single 

 dose of 1 mg. per gram of mouse) initiates, rather than promotes, the de- 

 velopment of pulmonary adenomas, and that the magnitude of the response 

 (i.e., the number of tumors initiated) is directly related to the rate of growth 

 of the animal at the time of exposure to urethane. This action of urethane 

 was markedly intensified by treatment of the mice with aminopterin and 

 greatly reduced by administration of a hydrolyzate of DNA. Further indi- 

 cations that, in some as yet undisclosed manner, urethane influences the 

 synthesis of nucleic acids, particularly the pyrimidines of DNA, was ob- 

 tained from ingenious experiments in which lung tissues from week-old mice, 

 prior to implantation in untreated mice, were incubated with the serum of 

 rabbits previously injected with urethane; the effect of other compounds 

 was determined by their addition to this test system. Thus, oxalacetate 

 increased the number of tumors obtained after implantation, while carba- 

 mylaspartate and asparagine (but not aspartate) diminished the number. 

 Although these findings might suggest a disturbance in the synthesis of car- 

 bamylaspartate, orotic acid, and subsequently formed pyrimidines, the re- 

 sults obtained in vivo do not indicate that the explanation is a simple one. 

 Thus, the oncogenic action of urethane, although greatly reduced by the 

 administration to the treated mice of orotic acid, cytidylic acid or thymine, 

 was affected but little or not at all by dosage with uracil, uridylic acid, or 

 deoxy cytidylic acid, while thymidine apparently was much less active than 

 thymine, although (as indicated previously) a remarkable effect was ob- 

 tained with hydrolyzates of DNA. 



These results, although confusing, have support, in part, from experi- 

 ments in which thymine (but not uracil) prevented the production of ab- 

 normal mitoses by urethane in the Walker tumor. 545 Similarly, in the studies 

 of the carcinostatic activity of urethane on the 755-tumor, considerable 

 reversal activity was reported for thymine, thymidine, cytidine, glutamine, 

 and asparagine, although with other metabolites the effects observed were 

 less marked or even negligible. Since the growth of adenocarcinoma-755 is 

 fraught with many difficulties and irregular results are sometimes obtained, 

 it may be unwise to draw extensive conclusions from these "reversal experi- 

 ments." 



In view of the fact that thymine is very poorly utilized for DNA thymine 

 synthesis (at least by the rat) and is very rapidly and extensively de- 

 graded, 546-549 the possibilities that this pyrimidine may be used in the for- 



544 S. Rogers, Federation Proc. 16, 370 (1957). 



545 E. Boyland and P. C. Roller, Brit. J. Cancer 8, 677 (1954). 



546 G. B. Brown, P. M. Roll, and H. Weinfeld, in "Phosphorus Metabolism" (W. D. 

 McElroy and B. Glass, eds.), Vol. II p. 385. Johns Hopkins Press, Baltimore, 

 Maryland, 1952. 



M1 W. H. Prusoff, W. L. Holmes, and A. D. Welch, J. Biol. ('hem. 209, 503 (1954). 



