Distribution and Effects of 4′, 4″-di(2-Imidazolin-2-yl) terephthalanilide Dihydrochloride Hemihydrate and Its 2-Chloro Analogue in Lymphocytic Leukemias L1210 and P3882

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Abstract
4′4″-di(2-imidazolin-2-yl)terephthalanilide dihydrochloride hemihydrate (NSC-35843) and its 2-chloro analogue (NSC-38280) represent a class of imidazolinylterephthalanilides highly active against a number of rodent neoplasms. Drug uptake by sensitive and resistant lines of the ascites and solid forms of L1210 lymphocytic leukemia has been determined with reference to the time after administration of the drugs to mice bearing the tumors. The resistant lines of the solid form of L1210 accumulated from 30 to 70 percent as much drug equivalents as the sensitive line after a course of delayed therapy. Studies on tumor growth and duration of survival of animals bearing the subcutaneous tumors showed that the phthalanilides increased length of survival but did not inhibit growth of the solid tumors significantly. Resistant lines of L1210 and P388 lymphocytic leukemias growing in the ascites form retained only 10 to 25 percent as much NSC-38280 as the sensitive cells 24 hours after drug administration in vivo. However, ½ hour after drug administration, drug levels were comparable in sensitive and resistant lines, and approximated the 24-hour drug levels in sensitive cells. Experiments in vitro also indicated no significant differences in the initial binding of NSC-38280 to sensitive or resistant ascites L1210 cells. Several lines of evidence suggested that NSC-38280 was not metabolically altered by L1210 or P388 cells. With both C14, abeled and unlabeled phthalanilide, essentially all the drug added in vitro to L1210 or P388 ascites cells was recovered chromatographically. The chromatograms of extracts of solid tumors from mice which had received NSC-38280 revealed no drug-related peak other than that of authentic NSC-38280. However, NSC-35843 appeared to undergo a change in vivo that decreased its basicity as determined chromatographically, but did not change its ultraviolet absorption characteristics. Such a chang was not found after incubation of the drug with sensitive or resistant P388 cells in vitro.