39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 463 



Folic acid antagonists have found their greatest field of usefulness in the 

 treatment of acute leukemia in children, although remissions have been 

 observed occasionally in other types of neoplasia. In many cases of acute 

 leukemia in children, the response to amethopterin is not sufficient for sig- 

 nificant remissions to develop. Although fair remissions are seen in perhaps 

 one-half to two-thirds of the cases, the number of "complete remissions," 

 in which the leukemic state appears (temporarily) to have been abolished, 

 is small. As a rule, the diagnosis is rarely made until the leukemic state is 

 well advanced, and infiltration of most of the tissues of the body with leu- 

 kemic cells may be .presumed to have occurred. In human neoplasias, a cure 

 appears never to have been attained following therapy with amethopterin, 

 or, for that matter, with other chemotherapeutic agents, used singly or in 

 combination. On the other hand, under some conditions, a high proportion 

 of mice inoculated with some types of leukemia cells can be cured with 

 amethopterin; however, this result usually is attained only with early treat- 

 ment following the introduction of a relatively small number of cells. Usu- 

 ally, antagonists of folic acid cause only a prolongation of the survival time. 

 Clearly, however, the action of amethopterin on many types of lympho- 

 blastic cells in mice is sufficiently selective to permit very favorable results 

 to be obtained despite the influence of this extremely toxic agent on some 

 cells of the mammalian host. 



Mouse leukemia cells (lymphoblasts L-5178-Y and mast cells P-815) re- 

 producing in culture have a very high requirement for folic acid, as com- 

 pared to other types of neoplastic and "normal" cells. However, the needs 

 of these leukemic cells can be met by minute amounts of folinic acid, a 

 finding which implies that the cells are deficient in the enzyme responsible 

 for the formation of FH 4 from F 2 . This circumstance may account for 

 the very high sensitivity to amethopterin of such cells, in vivo as well as 

 in culture. 57, 58 



The preferential incorporation of formate-C 14 into leukemic blood cells 

 of mice (in vivo) has been demonstrated by autoradiographic techniques. 59 ' 60 

 These studies indicated that the leukemic cells have a much more active 

 formate metabolism than the various normal cells of the blood. Studies 

 with similar mouse leukemic cells incubated in vitro demonstrated the in- 

 corporation of formate-C 14 into proteins and into the purine components 

 of nucleic acids; this incorporation was inhibited (though far from com- 

 pletely) by amethopterin. 61 



57 G. A. Fischer and A. D. Welch, Science 126, 1018 (1957). 



68 R. Schindler, M. Day, and G. A. Fischer, Cancer Research 19, 47 (1959). 



69 H. E. Skipper, J. B. Chapman, G. A. Boyd, W. H. Riser, Jr., and M. Bell, Proc. 

 Soc. Exptl. Biol. Med. 77, 849 (1951). 



60 H. E. Skipper, J. B. Chapman, and M. Bell, Proc. Soc. Exptl. Biol. Med. 78, 787 

 (1951). 



61 A. D. Williams, G. G. Slater, and R. J. Winzler, Cancer Research 15, 532 (1955). 



