Studies on the Management of Mouse Leukemia (L1210) with Antagonists of Folie Acid*

The current experiments were conducted: (a) to explore the possibility of obtaining extensive survival times, by treatment with folie acid antagonists against an acute transplantable leu kemia in mice; (6) to determine whether it is possible to obtain a significant number of leukemic mice which will survive as a result of antifolic therapy. In previous studies the principle was estab lished that the specificity of action of a drug, ex pressed in terms of its relative effect on host and tumor, is not static but can be altered by the manner in which the drug is employed (2-4, 6-8). Specificity of action is influenced by factors such as: (a) the time in the course of the disease at which treatment is initiated; (6) the spacing of the treatments; (c) the number of treatments; (d) the administration of a metabolite with an antagonist; (e) the age and weight of the animal. In each instance the extent of antitumor activity was dependent upon the inhibitory effect of the drug on the tumor relative to the toxic effect of the drug on the host. Several procedures were observed to increase the antileukemic specificity of action of the folie acid antagonists when treatment was initiated up to about 5 days following tumor inoculation. It was suggested that the employment of such procedures might provide a means whereby ex tended antileukemic effects could be produced. The suggested procedures were: (a) the use of spaced treatment ; for this purpose a 4-day spacing between treatments appeared to be an appropri ate interval (4, 7) ; (6) the delayed administration of citrovorum factor (CF) following treatment with the antagonist (3, 7). A 24-hour delay for administration of the metabolite appeared suitable; (c) the combination of spaced treatment of an-