39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 491 



Indeed, it was felt for some time that the selective action of azaguanine on 

 certain experimental tumors and its lack of toxic effect on naturally re- 

 sistant tumors, and on host organs such as liver and intestine, could be 

 attributed to the low levels of guanase in these latter tissues. 269 ' 27 ° How- 

 ever, all of the data are not in agreement with this general statement, and 

 other factors must be concerned with the susceptibility of various tissues 

 to this analog. 269 • 271 That the action of azaguanine is limited by guanase, 

 however, became apparent when a marked increase in azaguanine toxic- 

 ity 268, 272 and carcinostatic activity 273 was noted following the administra- 

 tion of aminoimidazolecarboxamide, a compound which acts not only as a 

 purine precursor but also as an excellent inhibitor of guanase. As pre- 

 dicted, 268 this resulted in greater incorporation of guanine into nucleic 

 acids when aminoimidazolecarboxamide was administered with gua- 

 nine. 2742741 



Although it is not a substrate for xanthine oxidase of milk, 275 or for aden- 

 osine deaminase from rabbit intestine and adenocarcinoma 755, 276 aza- 

 guanine is a potent inhibitor of these enzymes. With the deaminase it is 

 thought to combine in noncompetitive manner with the enzyme-substrate 

 complex. Such inhibition is well established by even subtherapeutic levels 

 of azaguanine administered to inact animals, 277 but the suggested connec- 

 tion between these findings and growth inhibition requires further substan- 

 tiation. 



As indicated above, the sites of action of azaguanine in nucleic acid 

 metabolism, or indeed in the complex phenomena of growth, are by no 

 means established. Despite its metabolic conversion to nucleotides, its 

 incorporation into nucleic acids, and changes in the pattern of utilization 

 of purines by cell lines resistant to this analog, the effects of azaguanine on 

 the incorporation of precursors into the purines of nucleic acids have not 

 yet afforded a satisfactory formulation of its mechanism of action. The 

 activities observed with azaguanine were the inhibition of the incorporation 



268 P. E. Carlo and H. G. Mandel, Cancer Research 14, 459 (1954). 



269 E. Hirschberg, J. Kream, and A. Gellhorn, Cancer Research 12, 524 (1952). 



270 E. Hirschberg, M. R. Murray, E. R. Peterson, J. Kream, R. Schafranek, and J. L. 

 Pool, Cancer Research 13, 153 (1953). 



271 B. Shacter and L. W. Law, J . Natl. Cancer Inst. 18, 77 (1957). 



272 P. E. Carlo and H. G. Mandel, J. Biol. Chem. 201, 343 (1953). 



273 H. G. Mandel and L. W. Law, Cancer Research 14, 808 (1954). 



274 L. L. Bennett, Jr. and H. E. Skipper, Cancer Research 17, 370 (1957). 



2744 H. G. Mandel, J. L. Way, and P. K. Smith, Biochim. et Biophys. Acta 23, 402 (1957). 

 276 P. Feigelson and J. D. Davidson, Cancer Research 16, 352 (1956). 



276 P. Feigelson and J. D. Davidson, J. Biol. Chem. 223, 65 (1956). 



277 J. E. Ultman and P. Feigelson, Cancer Research 18, 1319 (1958). 



