The nucleic acid inhibiting action of 4-amino-N10-methylpteroylglutamic acid in mice with a sensitive and resistant strain of leukemia.

that folic acid antagonists provide temporary palliation in certain cases of acute leukemia in children (7) and that several compounds of this class increase the survival time of mice with transplanted leukemia Ak 4 (4, 10, 11). However, eventual failure in the treatment of leukemia by chemotherapy with such compounds occurs consistently. The mechanism involved in the development of drug resistance in leukemia is at present poorly understood. The lack of fundamental knowledge on this point makes it difficult to utilize the known anti-leukemic agents to the fullest advantage. to sensitive strain of leukemia may be rendered resistant to 4-amino-N'°-methylpteroylglutamic acid (A-methopterin) by repeated passage through treated mice (5). This strain shows a cross resist ance to five other 4-amino antagonists of pteroyl glutamic acid (s). These observations may parallel the ultimate failure of folic acid antagonists in the treatment of patients with acute leukemia. Law and Boyle (9) have reported the develop ment of resistance in three separate sublines of a transplantable lymphoid leukemia in dba mice following successive transplants in mice treated with three different folic acid antagonists. These refractory strains carried over resistance from one antagonist to another. One of us has demon strated that a strain of mice made resistant to A-methopterin retained its sensitivity to the anti-leukemic effects of a crude antagonist of pteroylglutamic acid (3) and @,6-diaminopurine (6). Recent findings concerning the effect of folic acid antagonists on nucleic acid synthesis suggest that folic acid or some metabolite of this corn pound may be acting as the prosthetic group of an enzyme necessary for purine synthesis (8, 13). Certainly, A-methopterin or 4-aminopteroylglu tamic acid (aminopterin) exerts a profound inhib itory effect on nucleic acid synthesis in vivo (13). The following experiments were conducted with the thought in mind that the failure of the re sistant strain of leukemia to respond to A-methop tern might be due to a failure of this compound to inhibit sufficiently nucleic acid synthesis in the refractory leukemic cells. EXPERIMENTAL The 4-amino-N'°-methylpteroylglutamic acid resistant subline of mouse leukemia (Ak 4-R) used in these studies has already been described (5).This drug-fast strain showed no significant response to treatment with A-methopterin, while the original strain (Ak 4) responds to the extent that one ob serves a consistent increase in life span, in treated compared to untreated mice, of greater than 100 per cent. The method used to determine the rate of syn …