Some Effects of Nucleic Acid 

 Antimetabolites on the Central Nervous 

 System of the Cat* 



Harold Koemg 



Veterans Administration Research Hospital and 



Xorthuestern University Medical School. 



Chicago, Illinois 



Amont; the biolooic effects imputed to ionizini; radiation is a disturbance 

 in nucleic acid metabolism. The deleterious effect of ionizin" radiation on 

 DNA. particularly in proliferating tissues, is well known (Seed. 1960 i. Its 

 influence on RNA metabolism has received less attention, lliat it is not 

 without effect on the latter. howe\er. is suijgested by several recent studies 

 (Krogh and Bersjeder. 1957; Schummelfeder. 1957). It may be sci'mane to 

 this symposium to describe some of the effects of certain nucleic acid anti- 

 metabolites on the mammalian central nervous system. 



These studies had their inception in obser\ations made earlier with the aid 

 of taooed precursors which showed that neurons, olioodendroolia. and certain 

 other cells are site of acti\e RNA and protein turno\er i Koeni',;. 1958a,b). 

 A slow labeling of DNA also occurs among these cells, neurons excepted, 

 which probably indicates cell di\ision. We ha\e attempted to interlere with 

 these metabolic activities through the use of nucleic acid antimetabolites. 

 Intrathecal administration was used to circum\ent the blood-brain barrier 

 and to attain adequate local concentration of antimetabolities in the nervous 

 system without damaging hematopoietic and other susceptible tissues. Of many 

 purine and pyrimidine analogs tested, several ffuorinated pyrimidines were 

 tound to produce interesting neurologic disorders i Koenig, 1958ci. The 

 neurotoxic antimetabolites were 5-fluoroorotic acid i FO i , the analog of 

 orotic acid > the natural precursor of pyrimidines i and the ribosides. 5-fluoro- 

 uridine FUR) and 5-fluorocytidine FCR ) (Fig. 1 i. The pyrimidine bases, 

 5-fluorouracil • FU ) and 5-fluorocytosine i FC ) , were without overt effect, 

 even in large doses. The clinical, pathologic, and biochemical effects of these 

 analogs, particularly FO. on the feline neuraxis ha\e been imder inxestiga- 

 tion for several years. .Although their biochemical effects ha\e not been 



* Supported in part by grants from The U.S. Public Health Service and the .Atomic 

 Energy Commission. 



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