ANALOGUES 



benzoylglutamic acid, but quinoxaline-2-carboxylyl-_/)-aminobenzoyl- 

 glutamic acid and a substance formed by the reaction of dibromo- 

 propionaldehyde with o-phenylene diamine and ^-aminobenzoyl- 

 glutamic acid were also markedly inhibitory. Quinoxaline itself 

 inhibited the growth of S. faecalis R and the effect was reversed by 

 pteroyl glutamic acid.*^ 



According to Edwards et al.,^^ the benzimidazole corresponding to 

 pteroylglutamic acid, namely N-{4-[(2-benzimidazolylmethyl)-amino]- 

 benzoyl} -glutamic acid could replace folic acid as a growth factor for 

 S. faecalis R, although N-{4-[(2-benzimidazolylmethyl)-amino] -benzene 

 sulphonyl} -glutamic acid antagonised folic acid. King et al, ^^ how- 

 ever, found the former to have a slight inhibitory action on the growth 

 of both 5. faecalis R and L. helveticus ; the 5-chloro-derivative was 

 somewhat more active. Pteroylsulphoglutamic acid, N-[4-{[(2-amino- 

 4-hydroxy- 6 - pteridyl) - methyl] - amino} - benzenesulphonyl] -glutamic 

 acid slightly inhibited the growth of 5. faecalis, but did not antag- 

 onise the action of folic acid on this organism or on L. helveticus or S. 

 aureus .^'^ 



Folic Acid Antagonists and Cancer 



It has already been noted (page 501) that pteroylglutamic acid 

 and pteroyltriglutamic acid induce a sense of well-being in cancer 

 patients without having any inhibitory action on the growth of the 

 tumour. It was observed, however, that in animals a folic acid 

 deficient diet protected experimental animals against Rous chicken 

 sarcoma. ^^' ^^ This naturally led to tests being conducted with folic 

 acid antagonists, and it was found that pteroylaspartic acid, 4-amino- 

 N^^-methylpteroic acid and 4-amino-N^^-methylpteroylglutamic acid 

 were slightly effective, 4-aminopteroylaspartic acid markedly effective 

 and 4-aminopteroylglutamic acid most effective of all in preventing 

 the development of sarcoma.^* The lives of mice with transplanted 

 leukemia were prolonged when large amounts of crude 7-methylfolic 

 acid were given ^^ or when 4-amino-Ni^-methylpteroylglutamic acid, 

 4-amino-9-methylpteroylglutamic acid, 4 -amino- 9 : N^^-dimethyl- 

 pteroylglutamic acid or 2 : 6-diaminopurine were administered.^^ The 

 effect of 4-amino-Ni^-methylpteroylglutamic acid was blocked by prior 

 administration of 10 to 20 times the amount of pteroylglutamic acid.^^ 



One or two of these compounds, particularly Aminopterin, have been 

 tested in human leukemia, but the results have proved disappointing. 

 Occasional remissions were observed in some patients, but these were 

 only temporary and toxic symptoms were produced in many patients. ^^ 



Several of the above folic acid antagonists inhibited the growth of 

 crown gall tumour tissue on carrot fragments.^ ^ 



523 



