Investigation of the activity of cytoxan against leukemia L1210 in mice.

Two prime limiting factors in the treatment of neoplastic disease are (a) the toxicity of active anti-tumor agents for the host, and (b) the origin, during therapy, of resistance to the agent being employed. The origin of resistant variant sublines to therapy with folic acid antagonists, antipurines, glutamine antagonists, etc., has been amply demonstrated (5, 6, 22, 25-31, 86, 37). For purposes of overcoming the limitation of drug toxicity in therapy, a primary objective of screening programs and of detailed structureactivity studies within active groups of compounds has been to uncover drugs with increased antitumor activity and reduced host toxicity (7, 17, 21, 35, 39, 41). With respect to the origin of resistance to treatment, the effort has been twofold: (a) To uncover more active congeners within the same structural series (2, 7, 17, 41) and (b) to obtain drugs which inhibit at sites in different metabolic pathways or at different loci within the same metabolic pathway (8, 38, 40). Such compounds have been employed in clinical studies of concomitant and sequential therapy (9). Combinations of drugs presumed to act at different sites have been employed in studies of anti-tumor synergism, empirically or in attempts at multiple biochemical blockade (12). In this laboratory, assay procedures for the quantitative evaluation of chemotherapeutic agents have been developed with the use of early and advanced leukemia L1210 in mice (14, 15). With these procedures, various purine and pyrimidine antagonists, nitrogen mustard, and folic acid antagonists etc. (18), demonstrated definite therapeutic effectiveness. The folic acid antagonists were particularly effective in increasing the survival time of mice with this leukemia (17, 18). Although amethopterin was markedly effective in this system, it was surpassed in therapeutic activity by various halogenated derivatives of amethopterin (11, 17). Notably, two of the dihalogenated derivatives of amethopterin, 3'5'-