39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 457 



Early studies 19 of the effect of the administration of folic acid to adult 

 individuals with chronic myelocytic leukemia had indicated that such treat- 

 ment caused the clinical condition to deteriorate rapidly and the peripheral 

 "blast cell" count to increase markedly. Remissions apparently developed 

 in this disease when patients were given a diet low in folic acid, together 

 with a poorly absorbed sulfonamide (to inhibit the biosynthesis of folic 

 acid-derivatives by intestinal flora) and a weak competitive antagonist of 

 folic acid (so-called x-methylfolic acid). Also, in mice this antagonist was 

 used successfully to create a deficiency of folic acid 20 ; this state, in animals 

 with a transplanted acute lymphoblastic leukemia, significantly prolonged 

 the survival of the animals. 21 However, the first clinical findings of major 

 importance in the chemotherapy of leukemia were obtained with aminop- 

 terin; these showed that remarkable temporary remissions in the course 

 of some cases of acute leukemia in children could be induced by treatment 

 with this agent. 22 Even a decade later, no derivatives of folic acid have been 

 found which offer any significant advantages over aminopterin, except 

 perhaps amethopterin, and, with the exception of recent important findings 

 in choriocarcinoma in the human female, 23 ' 24 consistent inductions of tem- 

 porary remissions have not been reported with these agents in other types 

 of neoplastic disease of man. On the other hand, the striking results obtained 

 with amethopterin in a variety of transplantable neoplasms of animals, 

 particularly acute leukemias in mice, have led to much investigation of 

 this and related compounds. 



Recent advances in our knowledge of the compounds formed metaboli- 

 cally from pteroylglutamic acid and of their catalytic roles in a variety of 

 enzymic transformations indicate that the 4-amino derivatives of folic acid 

 are particularly effective inhibitors of the enzymic reduction of folic acid 

 (F) u to the tetrahydro form (FH 4 ), U i.e., 5,6,7,8-tetrahydropteroylglu- 

 tamic acid. Although these analogs of folic acid may interfere to some ex- 

 tent with other stages in the metabolic alteration of the vitamin, such in- 

 hibitions apparently are obtained only with higher concentrations. For 

 example, the growth of Pediococcus cerevisiae, an organism which uti- 



18 T. H. Jukes and H. P. Broquist, in "Metabolic Pathways" (D. M. Greenberg, 

 ed.), Vol. 2. Academic Press, New York, in press. 



19 R. W. Heinle and A. D. Welch, J. Clin. Invest. 27, 539 (1948). 



20 D. R. Weir, R. W. Heinle, and A. U. Welch, Proc. Soc. Exptl. Biol. Med. 69, 211 

 (1948). 



21 D. R. Weir, A. D. Welch, and R. W. Heinle, Proc. Soc. Exptl. Biol. Med. 71, 107 

 (1949). 



22 S. Farber, L. K. Diamond, R. D. Mercer, R. F. Sylvester, Jr., and J. A. Wolfe, 

 New Engl. J. Med. 238, 787 (1948). 



23 M. C. Li, R. Hertz, and D. B. Spencer, Proc. Soc. Exptl. Biol. Med. 93, 361 (1956). 



24 M. C. Li, R. Hertz, and D. M. Bergenstal, New Engl. J. Med. 259, 66 (1958). 



