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



ficiency, or of the absence of the product of the reaction, need not neces- 

 sarily imply that this is the site of action of the antimetabolite or, for that 

 matter, that it represents a reaction essential to the inhibitory activity of 

 the compound. 



Another aspect of the study of antimetabolites which requires careful 

 interpretation is the effect of "reversing" agents on growing cell systems. 

 Certain of the possible pitfalls were recognized early in the study of the 

 pyrimidine antimetabolites when nonphysiological compounds such as bro- 

 mouracil were shown to prevent the inhibitory action of other pyrimidine 

 analogs. Thus, prevention of the inhibitory action of an agent by another 

 chemical is by no means a certain indication that the latter is a natural sub- 

 strate, the formation or further metabolism of which is blocked by the com- 

 pound under consideration. Also, data which indicate either competitive 

 or noncompetitive inhibition by an antimetabolite of growth on the cor- 

 responding metabolite do not always reflect the actual mechanism of the 

 inhibitory activity of the agent on individual enzymes. 



One of the potentially most rewarding areas for further exploration is 

 the importance of multiple pathways leading to certain key intermediates 

 in the biosynthesis of nucleic acids; thus, more than one route to uridylic 

 acid, thymidylic acid, inosinic acid, adenylic acid, guanylic acid, and other 

 aucleotides is either known or suspected, but the factors influencing the 

 relative degrees of operation of these routes are but little understood. 

 Knowledge not only of the homeostatic factors which control these path- 

 ways, but also of ways to influence these alternate routes in vivo, for ex- 

 ample, by means of analogs of the normal homeostatic regulators, will have 

 practical as well as heuristic value. 



Finally, it is anticipated that in the next few years much more will be 

 discovered concerning the mechanisms by which macromolecules of nucleic 

 acid participate in protein synthesis and in the transfer of genetic informa- 

 tion. This entire area of function, as contrasted to synthesis, has been vir- 

 tually unexplored from the standpoint of antimetabolites and may in the 

 future represent a most rewarding field of study. 



