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



of formate 4 • 278 and glycine 3 • 279 into guanine (but not adenine) of the nu- 

 cleic acids of tumors or internal organs of mice. Similarly, incorporation of 

 phosphate-P 32 into the DNA of adenocarcinoma 755 of mice treated with 

 azaguanine was slightly reduced, 2 but uptake into Flexner-Jobling tumors 

 in rats treated with this compound on a different dosage schedule, was stimu- 

 lated. 4 The incorporation of adenine 233 ' 279 ' 280 or guanine 272 into nucleic 

 acids, and their interconversion 233 in several systems, were essentially un- 

 affected by azaguanine, a surprising result when compared to the growth 

 experiments in which guanine proved to be a good reversing agent. Perhaps 

 one of the most striking actions of this analog is the reproducible increase 

 in the content of ribonucleic acid per cell which has been noted with B. 

 cereus, 260 since it appears that this "extra" RNA is abnormal material in 

 which a high percentage of the guanine is replaced by azaguanine. Con- 

 firmatory increases in the uptake of guanine and hypoxanthine, 179 glycine, 3 

 uracil, 281 and radioactive phosphate 4 have been reported in this and other 

 systems. These results, coupled with increases in the nucleotide pools of 

 tumor and liver, 282 and of S. faecalis, 179 have suggested that the primary 

 effect of azaguanine is probably not on the early stages of purine nucleotide 

 synthesis but on the organization and function of nucleic acids and purine- 

 containing coenzymes. 



One likely result of the suggested effect of azaguanine would be disrup- 

 tion of protein synthesis. Supporting this idea was the greater inhibition of 

 the uptake of methionine or cystine 283 in B. cereus than of growth. Incor- 

 poration of other amino acids, such as lysine, valine, and histidine, also was 

 strongly inhibited, while the uptake of aspartic acid and leucine was essen- 

 tially unchanged, and that of serine and alanine was greatly stimulated. 284 

 Such results suggest a considerable disorganization of normal protein syn- 

 thesis and perhaps amino acid exchange following exposure to azaguanine. 

 Similar studies by another group would appear to indicate that intracellu- 

 lar protein synthesis is interrupted by the analog, but that the formation 

 of cell wall material continues essentially unaltered, as does the production 

 of DNA. 281 ' 285 As noted above, the production of RNA increases, but this 

 probably represents an abnormal form of RNA in that it is rapidly degraded, 

 with rejection of the analog from the RNA, when the cells are removed to 



278 H. E. Skipper, J. H. Mitchell, Jr., L. L. Bennett, Jr., M. A. Newton, L. Simpson, 

 and M. Eidson, Cancer Research 11, 145 (1951). 



279 R. Abrams, Arch. Biochem. Biophys. 33, 436 (1951). 



280 J. L. Way, H. G. Mandel, and P. K. Smith, Cancer Research 14, 812 (1954). 



281 H. Chantrenne and S. Devreux, Nature 181, 1737 (1958). 



282 P. A. Zahl and H. G. Albaum, Proc. Soc. Exptl. Biol. Med. 88, 263 (1955). 



283 H. G. Mandel, Arch. Biochem. Biophys. 76, 230 (1958). 



284 D. B. Roodyn and H. G. Mandel, Federation Proc. 18, 439 (1959). 

 286 H. Chantrenne, Biochem. Pharmacol. 1, 233 (1959). 



