Estimation of the antileukemic potency of the antimetabolite aminopterin, administered alone and in combination with citrovorum factor or folic acid.

Administration of citrovorum factor (CF) or pteroylglutamic acid (FA) may reduce the lethal toxicity for mice of the antimetabolite 4-aminopteroylglutamic acid (aminopterin). The mortality response is dependent upon the relative dose level of FA or CF administered with the aminopterin and is influenced by the temporal relationships of administration of the drugs (1, 8-12). Administration of FA or CF may also interfere with the tumor inhibitory effects of 4-amino FA derivatives (2, 3, 5, 13, 14). However, the tumor studies were confined to the effect of FA and CF on the therapeutic action of a dose of antagonist in the range of the maximum tolerated dose on mul tiple treatment. Consideration was not given to the relationship of host toxicity to antitumor ac tivity of the drugs. Since toxicity of aminopterin to the host has constituted a limiting factor in the treatment of neoplasia, studies were undertaken to determine in what manner the quantitative host-toxicity rela tionships demonstrated with FA, CF, and ami nopterin may relate to their effects on the growth of tumor. In this investigation a comparison is made of the relative effectiveness of the following treatments in prolonging the survival time of mice with a transplantable leukemia. a) Aminopterin alone. 6) Aminopterin plus concomitantly adminis tered CF. c) Aminopterin plus FA, when the FA is ad ministered 1 hour prior to the aminopterin.