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



[e.g., 2,4-diamino-5(3',4'-dichlorophenyl)-6-methyl-pyrimidine] and the analogous 

 triazines to inhibit hematopoiesis and, particularly, to cause leucopenia has been 

 investigated in several animal species and in patients with leukemia. 98103 These ac- 

 tivities and the toxicity of the compounds appear to be exerted in a manner resem- 

 bling that of amethopterin; analogous conclusions may be drawn from studies of the 

 diaminodihydrotriazines. However, direct studies of the effect of these agents on the 

 folic acid reductases, analogous to those described with amethopterin, have not been 

 reported. 



An interesting situation is found in the RH strain of Toxoplasma, for this patho- 

 genic organism probably obtains its supply of coenzymes related to FH 4 exclusively 

 from small molecular precursors, since sulfadiazine inhibits significantly the progress 

 of infections with this organism (in mice), an effect prevented by p-aminobenzoic 

 acid, but only very ineffectively by folic acid or even folinic acid. 104 The inefficiency 

 of action of the latter compounds may be attributed to the absence of a system in 

 the parasite for the utilization of these substances; in fact, traces of activity in these 

 compounds probably reflect the presence, or the catabolic formation in the tissues 

 of the mouse, of utilizable derivatives of p-aminobenzoic acid. This suggestion is 

 made more reasonable by the fact that the course of infections in mice with this Toxo- 

 plasma also is not affected by aminopterin. 104 105 However, the progress of the dis- 

 ease is inhibited by sulfonamides to about the same extent as by pyrimethamine, and 

 it has been suggested that the diamino-pyrimidine affects a stage in the intracellular 

 synthesis de novo of FH 4 (or its functional derivatives) by the parasite. Studies of 

 combinations of a sulfonamide and pyrimethamine have demonstrated marked syn- 

 ergistic activity, since cures could be obtained in mice with the combinations, whereas 

 only a delay in the progress of the lethal infection was obtained with either drug 

 alone. It is of considerable interest that the therapeutic efficiency of the combination 

 was not impaired, either in the mouse or in man, by the simultaneous administration 

 of folinic acid and yeast, while the occurrence of thrombocytopenia and leucopenia 

 was prevented. 



These important observations offer much encouragement to those interested in the 

 logical development of agents which can attack certain types of cells selectively or 

 the undesirable effects of which on normal or host cells can be nullified or minimized 

 selectively. 



A striking synergism also has been observed between the dihydrotriazines and 

 sulfadiazine in the therapy of experimental infections in mice with Diplococcus pneu- 



97 G. E. Foley, Proc. Soc. Exptl. Biol. Med. 83, 740 (1953). 



98 A. D. Welch, in "Cellular Metabolism and Infections" (E. Racker, ed.), Part I, 

 p. 61. Academic Press, New York, 1954. 



99 M. N. Swaffield, G. E. Foley, E. J. Modest, and C. L. xMaddock, Proc. Am. Assoc. 

 Cancer Research 3, 68 (1959). 



100 L. H. Schmidt, H. B. Hughes, and I. G. Schmidt, J. Pharmacol. Exptl. Therap. 

 107, 92 (1953). 



101 R. J. Dern, E. Beutler, J. Arnold, A. Lorincz, M. Block, and A. S. Alving, Am. J. 

 Trop. Med. Hyg. 4, 217 (1955). 



102 M. L. Murphy, R. R. Ellison, D. Karnofsky, and J. H. Burchenal, J. Clin. Invest. 

 33, 1338 (1954). 



103 S. Farber, R. Toch, E. M. Sears, and I). Pinkel, Advances in Cancer Research 4, 1 

 (1956). 



104 J. K. Frenkel and G. H. Hitchings, Antibiotics & Chemotherapy 7, 630 (1957). 



105 L. G. Goodwin and I. M. Rollo, in "Biochemistry and Physiology of Protozoa" 

 (S. H. Hutner and A. Lwoff, eds.), Vol. 2, p. 225. Academic Press, New York, 1955. 



