39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 471 



moniae, Type II. 106 In this disease, unlike toxoplasmosis, a synergism can be demon- 

 strated between aminopterin and either sulfadiazine or the dihydrotriazines. Similar 

 studies of a wide variety of pathogenic microorganisms has indicated that certain 

 streptococci are particularly susceptible to a diaminodihydrotriazine and that the 

 action of the latter is potentiated markedly by a sulfonamide in experimental in- 

 fections. 107 



A consideration of resistance to compounds of the diaminodihydrotriazine and 

 diaminopyrimidine types is of considerable theoretical and practical importance, 

 since cross-resistance between these agents is usually quite marked. Not only does 

 this finding support the concept of a common mechanism of action, but also it has 

 practical significance in that the relatively easy development of resistance of malarial 

 Plasmodia to the relatively weak agent, chloroguanide, predisposes them to much 

 more rapid development of resistance to the more potent agent, pyrimethamine. 98 



Of considerable interest to the problem of resistance to the diaminopyrimidines is 

 the finding, in a strain of S. faecalis selected for its ability to grow in a 1,000-fold 

 greater concentration of pyrimethamine than the parent strain, that following ex- 

 posure to folic acid, materials related to that substance could not be extracted from 

 the cells. However, following exposure of the sensitive cells to the same concentra- 

 tions of folic acid, the folic acid-like compounds were recovered quantitatively. The 

 resistant strain may be one which possesses the ability to bind assimilated folic acid 

 within the cells. 108 



The conclusion that the diaminopyrimidines and the diaminodihydrotriazines act 

 primarily by interfering with the formation of a coenzyme related to tetrahydrofolic 

 acid is supported by recent findings in mice with P-1534 leukemia. In these experi- 

 ments, the prolongation of survival and the toxicity caused by a diaminodihydro- 

 triazine were nullified by the coadministration of folinic acid, but not by therapy 

 with folic acid." On the other hand, as the result of recent studies with Lactobacillus 

 arabinosus, it was concluded that diaminodihydrotriazines compete with DPN, not 

 with pteroylglutamic acid (PGA), in a DPN-mediated reduction of a folic acid-like 

 compound. 106 An even greater complication has been introduced by the finding, with 

 S. pyogenes (C-203) grown in a chemically defined medium, that the inhibitory ac- 

 tivity of diaminodihydrotriazines is not prevented by either folic or folinic acids, 

 although a combination of acetate and DNA (or of acetate, deoxyguanylic acid, and 

 thymidine, but not of acetate and RNA) is effective. 109 



Although the mechanism of action of the diaminodihydrotriazines may not be 

 precisely the same in all forms of life, it may be concluded that the actions of these 

 compounds are directed primarily against the formation of coenzymes concerned with 

 the transfer of one-carbon intermediates and therefore with the synthesis of nucleic 

 acids. 



III. Compounds Which Interfere with Amination Reactions in 

 Purine and Pyrimidine Synthesis 



The potential importance of compounds which interfere with amination 

 reactions in the synthesis of nucleic acid precursors will be indicated by a 

 consideration of the role of glutamine in the synthesis of purine and pyrim- 



106 G. E. Foley, E. J. Modest, J. R. Cataldo, and H. D. Riley, Biochem. Pharmacol. 

 3, 18 (1959). 



107 M. W. Fisher and L. Doub, Biochem. Pharmacol. 3, 10 (1959). 



108 R. C. Wood and G. H. Hitchings, Federation Proc. 17, 339 (1958). 



109 V. M. McGlohon and O. O. Bird, Biochem. Pharmacol. 2, 299 (1959). 



