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Relationship of Uptake and Binding of an Antileukemic Phthalanilide to Its Biochemical and Chemotherapeutic Effects on P388 Lymphocytic Leukemia Cells¹

Life Sciences Division, Arthur D. Little, Inc., Cambridge, Massachusetts

An antileukemic phthalanilide, 2-chloro-4',4''-di(2-imidazolin-2-yl)terephthalanilide (NSC 60339), was taken up by P388 lymphocytic leukemia cells growing in culture. The uptake was related to the extracellular concentration of drug and the length of exposure to drug. The drug was extracted from the cells in 3 forms: lipid-bound, hydrophilic-bound, and "free." The levels of both bound components correlated significantly with the chemotherapeutic response, and it was found by multiple regression analysis that the chemotherapeutic response was related to the level of the lipid-bound component, less related to the hydrophilic-bound drug, and not related to the level of the "free" drug.

In addition, the inhibitions of biosynthetic capabilities of treated cells (DNA, RNA, protein, and lipid synthesis) were compared with intracellular drug concentration and with chemotherapy. Inhibition of DNA and protein synthesis occurred at drug concentrations which did not elicit a chemotherapeutic response; inhibition of lipid and RNA synthesis occurred at higher intracellular drug levels which killed the cells and therefore prolonged the life of the host mice. At intracellular drug concentrations which resulted in pronounced chemotherapy, DNA and lipid syntheses were completely inhibited, but RNA and protein syntheses were not.

¹ Supported by the Cancer Chemotherapy National Service Center, Contract No. SA-43-ph-3789, National Cancer Institute, NIH, USPHS.

Received 5/27/66. Accepted 9/ 2/66.