Studies of the mechanism of resistance to folic acid antagonists by leukemic cells.

The effectiveness of aminopterin and Amethopterin in those cases of acute leukemia in children which respond to these agents appears to be nullified eventually by the development of drug resistance (28). The metabolic characteristics which enable the resistant leukemic cell to cir cumvent the effect of the drug are not clearly understood. Direct comparison of antagonistsensitive and -resistant cells has been facilitated greatly by the development of antagonist-resistant leukemias in mice (3, 17) and antagonist-resistant strains of certain bacteria (5, 10). Studies of an A-methopterin-resistant strain of S. faecalis have indicated two mechanisms which may enable this organism to survive in the presence of high con centrations of this toxic compound. The antago nist-resistant cells were characterized by a re markable capacity to utilize pteroylglutamic acid (PGA, folie acid) for the formation of citrovorum factor (CF, folinic acid) (1, 11, 23), a compound which is very much more effective than PGA in counteracting the effect of the antagonists (2, 8, 21, 25, 26). Also, the enzymatic formation of CF from PGA by "sonic" extracts of the resistant cells was very sensitive to inhibition by the 4-amino analogs of PGA, in contrast to the high concentra tions of these antagonists which were required to inhibit the same reaction in the intact cells (19, 20, 22). The resistant bacterial cells appeared to acquire the ability to limit penetration of the an tagonists or in some other manner to render a susceptible enzyme less accessible to the antago nists. These studies were undertaken to determine the extent to which the changes observed in Amethopterin-resistant bacteria might apply to leukemic cells which are resistant to the folie acid antagonists.