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



mation of substances other than DNA thymine, or may exert indirect ef- 

 fects (rather than play only a precursory role), should be eliminated. An 

 additional complication is the antagonism by diaminopurine of the inhibi- 

 tion of the growth of E. coli by urethane (or by dimethylformamide). 324 ' 325 

 Despite the suggestion 550 that urethane influences "the formation of the 

 pyrimidine nucleus from carbamyl phosphate and aspartic acid, the meth- 

 ylation and the animation of the uracil moiety," much more work will be 

 needed to explain satisfactorily the remarkable effects of this compound on 

 nucleic acid metabolism. 



2. Miscellaneous 



It is evident that the discussion of agents which influence nucleic acid 

 metabolism presented thus far has dealt primarily with structural analogs 

 of compounds intimately associated with the assembly of the nucleotide 

 units. However, in addition to this group there must be a vast number of 

 substances which in one way or another can alter metabolism of the nucleic 

 acids. A few examples, illustrative of certain classes of such agents, will 

 indicate the diversity of these various factors. 



It is axiomatic that most general cellular poisons interrupt synthesis of 

 the macromolecules; however, evidence is accumulating which suggests that 

 the so-called alkylating agents, such as the nitrogen mustards 551 may prefer- 

 entially alkylate the phosphate groups of RNA and DNA and thereby exert 

 their radiomimetic action. Damage to body organs, such as the liver, by 

 carbon tetrachloride, results in a secondary regenerative phase in which 

 nucleic acid synthesis is markedly stimulated preparatory to a sharp in- 

 crease in mitotic activity within the organ. 552 Another compound, A^-dieth- 

 ylnicotinamide (nikethamide), has been reported to cause hyperplasia of 

 the liver in rats, an effect accompanied by increased incorporation of phos- 

 phate-? 32 into nucleic acids 553 ; whether this represents tissue proliferation 

 in response to injury cannot be stated. The carcinogen, acetylaminofluorene, 

 when fed to rats, creates a preneoplastic state in the liver during which the 



648 P. Reichard, Acta Chem. Scand. 9, 1275 (1955). 



549 K. F. Fink, R. E. Cline, R. B. Henderson, and R. M. Fink, J. Biol. Chem. 221, 



425 (1956). 

 650 G. B. Elion, S. Bieber, and G. H. Hitchings, Abstr. 7th Intern. Cancer Congr., 



London, p. 235 (1958). 



551 K. A. Stacey, M. Cobb, S. F. Cousens, and P. Alexander, Ann. N. Y. Acad. Sci. 

 68, 682 (1958). 



552 J. Hoffman, M. B. Hines, S. Lapan, R. Rizki, and J. Post, A.M. A. Arch. Pathol. 

 59, 429 (1955). 



653 W. R. Foster and F. G. Brazda, Cancer Research 18, 289 (1958). 



