160 PTEROYLGLUTAMIC ACID 



low in PGA or by the administration of 4-amino PGA (Little et al}'^). The 

 growth of this tumor is also reduced by deficiencies of other vitamins such 

 as nicotinic acid, pantotlienic acid, riboflavin,'"'* and vitamin B12 .'"'' PGA 

 exerted the greatest effect and was the only vitamin, a deficiency of which 

 completely prevented tumor growth. 



Similar to the effect of PGA antagonists on virus-induced tumors in 

 animals is their inhibiting action on growth of plant tumors. 4-amino PGA 

 and three other methylated derivatives of this antagonist were effective in 

 suppressing the growth of tumorous tissue induced on carrots by inoculation 

 with crown gall bacteria (de Ropp^'^^). 



The action of 4-amino PGA in normal and in leukemic animals has been 

 studied in great detail by the workers at Sloan-Kettering Institute.'"'^' '"^ 

 In a study of ninety compounds related to PGA only four showed definite 

 chemotherapeutic effect as measured by doubling the survival time of leu- 

 kemic Ak4 mice. These compounds were 4-amino-lO-methyl PGA, 4-amino- 

 9-methyl PGA, 4-amino-9 , 10-methyl PGA, and 2 , 6-diaminopurine. 4-am- 

 ino-PGA and 4-aminopteroylaspartic acid were less effective (Burchenal 

 et al.^^). In each case the compounds were given at the maximum tolerated 

 dose. In the treatment of a solid tumor, sarcoma 180, 4-amino PGA and 

 4-amino- 10-methyl PGA were the most effective, 4-aminopteroylaspartic 

 acid, pteroylaspartic, and pteroyltriglutamic acid being ineffective (Stock 

 et al}^''). The narrow margin between toxic and therapeutic dose is reflected 

 in the fact that in the case of 4-amino-lO-methyl PGA 1.0 mg. per kilogram 

 of body weight per day shows no activity, 2.0 mg. is markedly toxic, and 

 1.5 mg. gives marked inhibition of tumor activity with little evidence of 

 toxicity. 



One of the problems associated with clinical use of the PGA antagonists 

 in the treatment of leukemia is the eventual failure of therapj^ due to de- 

 velopment of resistance to this agent. If this resistance could be overcome, 

 the leukemia could conceivably be held indefinitely in check by use of the 

 therapeutic agent. This problem of resistance has been studied by the 

 development of a resistant strain of lymphoid leukemia, Ak4, by repeated 

 passage through mice treated with 4-amino- 10-methyl PGA (Burchenal 



'«2 P. A. Little, A. Sampath, V. Paganelli, E. Locke, and Y. SubbaRow, Trans. N. Y. 



Acad. Set. 10, 91 (1948). 

 '"3 p. A. Little, J. J. Oleson, and Y. SubbaRow, J. Lab. Clin. Med. 33, 1139 (1948). 

 104 J. J. Oleson and P. A. Little, Proc. Soc. Exptl. Biol. Med. 71, 226 (1949). 

 i»= R. S. de Ropp, Nature 164, 954 (1949). 

 "« F. S. Philips, J. B. Thiersch, and F. C. Ferguson, Ann. N. Y. Acad. Sci. 52, 1349 



(1950). 

 i"' C. C. Stock, J. J. Biesele, J. H. Burchenal, D. A. Karnofsky, A. E. Moore, and K. 



Sugiura, Ann. N. Y. Acad. Sci. 52, 1360 (1950). 



