39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 455 



knowledge of reactions involved in the formation of macromolecules and 

 their roles in cellular function, a broader outlook may be employed and 

 that new concepts in the design of antimetabolites eventually will evolve. 



It has been interesting as well as disquieting to observe the facility with 

 which bacterial and neoplastic populations of cells become immune to the 

 action of most of the compounds to be discussed. Through investigation of 

 the mechanisms of resistance to nucleotide antimetabolites, shifts in the 

 balance between the utilization of preformed purine or pyrimidine deriva- 

 tives and their synthesis de novo have been detected. The many factors 

 which control such balances are at present largely unknown and increased 

 research endeavor will be needed to disclose them and to explain their func- 

 tional interrelationships. 



As will be apparent in the discussion of individual agents, it is impossible 

 to consider the sites of actions of antimetabolites without giving proper 

 attention to their physiological disposition, since the primary motivation 

 for the development of these compounds is the treatment of disease states 

 and the more complete elaboration of the biochemical foundations of such 

 states. Thus, the failure of some of the extremely active compounds to be 

 transported into some areas of the body (e.g., the brain), into which neo- 

 plastic cells may penetrate very early following the development of a ma- 

 lignancy, has limited very severely their potential effectiveness. In addition, 

 metabolic alteration plays a major role in the activation of a number of the 

 agents to be discussed; this generally proceeds through the enzymic con- 

 version of the analog to a fraudulent mononucleotide, oligonucleotide or 

 even nucleic acid, in order to form the presumed biologically active inhibi- 

 tor. Catabolism of certain analogs, though frequently neglected, may ac- 

 count for the limitation of the action of these agents in intact animals, as 

 does the velocity of renal excretion in certain cases. Finally, variations in 

 tissue distribution and in the metabolic activities of various cell types may 

 give rise to a selectivity of action which could not be predicted from studies 

 with isolated enzymes. 



Several excellent reviews have appeared on the various aspects of the 

 topics to be discussed and should be consulted for detailed information 

 concerning these agents. 6 " 10 The present chapter is not intended to offer a 

 complete coverage of the literature; rather, it attempts to present some of 

 the highlights of the research on compounds of either chemotherapeutic or 

 more fundamental interest which influence some aspect of nucleic acid me- 

 tabolism. 



6 J. A. Montgomery, Cancer Research 19, 447 (1959). 



7 R. E. F. Matthews, Pharmacol. Revs. 10, 359 (1958). 



8 H. G. Mandel, Pharmacol. Revs. 11, 743 (1959). 



9 H. E. Skipper and L. L. Bennett, Jr., Ann. Rev. Biochem. 27, 137 (1958). 



10 W. Shive and C. G. Skinner, Ann. Rev. Biochem. 27, 643 (1958). 



