214 PTEROYLGLUTAMIC ACID 



(Aminopterin) are induced. Thus the much more rapid turnover of leuco- 

 cytes and thrombocytes than of circulating erythrocytes is reflected by the 

 early development of profound leucopenia and thrombocytopenia during 

 antagonist administration. These changes, if not arrested, lead to the fatal 

 complications of infection and hemorrhage before the effects of erythro- 

 poietic depression have time to become manifest in great degree. That 

 alterations in red cell production, similar to those seen in megaloblastic 

 anemias, do occur after antagonist administration was first pointed out by 

 Thiersch and Philips. '^^^ However, the extensive changes in tissues other 

 than those concerned with hemopoiesis, especially mucosal ulceration and 

 hemorrhage, may be attributed to the predominant mode of action of the 

 4-amino analogs of PGA. The virtual impossibility of reversing the action 

 of aminopterin and similar antagonists by any amount of PGA which is 

 feasible to administer had impressed many observers as an argument 

 against the concept of such compounds being true PGA antimetabolites. 

 The problem was solved by Nichol and Welch,^^- who showed that the 

 conversion of PGA to CF in vitro and in vivo is blocked by the presence of 

 aminopterin. The major metabolic effect of this compound is, therefore, 

 inactivation of an enzyme catalyst concerned with the biologically essential 

 PGA —> CF reaction. These authors also showed that the effects of such 

 antagonists could readily be reversed by the administration of CF, an 

 observation soon confirmed by others.^^^'^^^ 



Since the prevention or reversal of the action of aminopterin by CF is 

 accomplished when the compounds are given in fairly well-defined ratios, 

 it may be concluded that aminopterin competes with CF in biological sys- 

 tems which require this factor. 



In the words of Welch and Heinle :^^^ "It is evident, therefore, that 

 aminopterin exerts two quite different types of antagonism. That which 

 is related to the citrovorum factor is competitive and readily reversible, 

 while that concerned with folic acid is essentially non-competitive and only 

 reversible under conditions where very high concentrations of folic acid 

 are attainable. Obviously, therefore, the practical means of attempting 

 to reverse the toxic actions of the 4-amino analogues of folic acid involve 

 the use of citrovorum factor, but the principal reason for the development 

 of the toxic effects of the analogues when folic acid is administered is the 

 blockade of the biological utilization of the vitamin." 



2H J. B. Thiersch and F. S. Philips, Proc. Soc. Expfl. Biol. Med. 71, 484 (1949). 

 2'2 C. A. Nichol and A. D. Welch, Proc. Soc. Exptl. Biol. Med. 74, 403 (1950). 

 2>3 H. P. Broquist, E. L. R. Stokstad, and T. H. Jukes, /. Biol. Chem. 185, 399 (1950). 

 2" J. H. Burchenal, G. M. Babcock, H. P. Broquist, and T. H. Jukes, Proc. Soc. Exptl. 

 Biol. Med. 74, 735 (1950). 



215 E. B. Schoenbach, E. M. Greenspan, and J. Colsky, J. Am. Med. Assoc. 144, 155S 

 (1950). 



