39. ANTIMETABOLITES ANT) NUCLEIC ACID METABOLISM 479 



The early microbial experiments with L. casei and S. faecalis, microor- 

 ganisms which have absolute purine requirements in the absence of folic 

 acid, defined the specific anti-purine action of this compound. The inhibi- 

 tion of growth caused by mercaptopurine could be reversed in both or- 

 ganisms by the four natural purines, hypoxanthine, xanthine, adenine, and 

 guanine. 166 - 168 In a medium containing pteroylglutamic acid, xanthine was 

 the most effective agent in overcoming mercaptopurine inhibition in S. 

 faecalis and a strain selected for resistance to this analog was unable to 

 utilize adenine, guanine, or hypoxanthine for growth in the absence of 

 pteroylglutamic acid, while xanthine remained active as a purine source 

 and as a reversing agent for mercaptopurine toxicity. 168 Such data led to 

 the view 169 that one of the primary sites of action of mercaptopurine may 

 lie in the intercon version of guanine and adenine nucleotides through a 

 hypoxanthine derivative, as was recently demonstrated. 114 This concept is 

 supported by the accumulation of a large amount of inosine and hypoxan- 

 thine following growth of a mercaptopurine-resistant strain (MPR) of L. 

 casei in a medium containing adenine-8-C 14 . 170 More recently, purine me- 

 tabolism has been studied in growing cultures of strains of S. faecalis which 

 were either sensitive or resistant to the inhibitory action of the purine 

 analogs, mercaptopurine and azaguanine. The resistant strains varied 

 greatly in their ability to utilize guanine or hypoxanthine for the synthesis 

 of the purines of nucleic acids, but could incorporate adenine into the 

 adenine of nucleic acid, and xanthine into both of the purines of nucleic 

 acids. 171 ' m Similar studies with a subline of L-1210 leukemia which was 

 selected for resistance to mercaptopurine and azaguanine revealed marked 

 depression in the metabolism of guanine or hypoxanthine, but little change 

 in the utilization of adenine. 173 However, it has not been established un- 

 equivocally that the nutritional and, in fact, even the enzymic differences 

 between drug-sensitive strains and resistant sublines are related to the 

 mechanism of action of an antimetabolite, although it is probable that this 

 is the case. Certainly, such studies have great value in achieving an under- 

 standing of the mechanism of resistance and thereby in suggesting means 

 of circumventing this ubiquitous problem in chemotherapy. 



166 G. B. Elion, S. Singer, G. H. Hitchings, M. E. Balis, and G. B. Brown, ./. Biol. 

 Chem. 202, 647 (1953). 



167 G. B. Elion, S. Singer, and G. H. Hitchings, Ann. N. Y. Acad. Set. 60, 200 (1954). 



168 D. J. Hutchison, Ann. N. Y. Acad. Sci. 60, 212 (1954). 



169 G. B. Elion, S. Singer, and G. H. Hitchings, J. Biol. Chem. 204, 35 (1953). 



170 G. B. Elion and G. H. Hitchings, Federation Proc. 13, 203 (1954). 



171 D. J. Hutchison, Cancel- Research 18, 214 (1958). 



172 M. E. Balis, V. Hylin, M. K. Coultas, and D. J. Hutchison, Cancer Research 18 

 220 (1958). 



173 R. W. Brockman, C. Sparks, M. S. Simpson, and H. E. Skipper, Biochem. Pharma- 

 col. 2, 77 (1959). 



