128 Essays in Biochemistry 



organism, also found that 8-azaguanine was a growth inhibitor of 

 T. geleii by competition with guanine. 16 He then discovered that this 

 same compound would inhibit the growth of certain mouse tumors. 

 How or why this drug inhibits tumors is still unknown." Tumors 

 inhibited by 8-azaguanine are not arrested metabolically ; their nucleic 

 acid turnover is approximately the same as uninhibited tumors. Doses 

 of the drug which might be large enough to effect cure cannot be 

 tolerated by the host. The drug has absolutely no effect on some tumor 

 types such as sarcoma 180. Thus all tumors are not the same, and the 

 selection of tumors for experimentation is not entirely a matter of 

 convenience or indifference. 



8-azaguanine, nevertheless a good experimental carcinostatic agent, 

 is useless for human therapy because of its limited solubility and 

 because of its toxicity. These objectionable features led to a number 

 of synthetic maneuvers in an effort to increase the solubility of the 

 active groups, to decrease the toxicity, and above all to increase the 

 activity. Acetylation of the OH group proved to be futile; the ester 

 was inactive biologically, apparently because hydrolysis did not occur 

 with sufficient speed. Neoazaguanine, the sulfoxalate (by analogy with 

 neoarsphenamine) was also inactive. What was most disappointing, 

 however, was the inertness of the two pyrazolopyrimidines, 5-amino-7- 

 hydroxypyrazolo-4,3-d-pyrimidine and 6-amino-4-hydroxy-pyrazolo- 

 3,4-d-pyrimidine, both isomeric with guanine. 



The high expectations for the latter compounds arose from an overly 

 naive reliance on the applicability of competitive inhibition to a com- 

 pletely unknown metabolic system. A competitor is an agent which 

 differs so subtly from a required metabolite that it is accepted without 

 discrimination in the initial incorporative reaction. It is only in the 

 events which follow the diversion of enzymes that the cell discriminates 

 between the true and the false, and biosynthesis grinds to a halt. If 

 the proffered compound differs so subtly from its natural analog, 

 there may be no distinction at all and the cells may utilize the substi- 

 tute with equal facility. If, on the other hand, the alteration is too 

 gross the compound is completely ignored in the first instance. Even 



* One could now surmise that 8-azaguanine acts by inhibiting an oxidatively 

 generated factor. If this were true, it would follow that the drug would act 

 synergistically with hypoxia, and that its toxicity would be diminished after 

 acclimatization of the host to hypoxia. Furthermore, Drs. Philip Feigelson and 

 J. D. Davidson of this institution have adduced strong evidence that the car- 

 cinostatic activity of 8-azaguanine depends on its capacity to inhibit xanthine 

 oxidase which appears to be necessary for the biosynthesis of guanine. (Personal 

 communication.) 



