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Modulation of the Cellular Toxicity of Nitrogen Mustard in Murine Cells

Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania 19104

A linear increase in cell uptake of nitrogen mustard, methyl-bis(ß-chloroethyl)amine (HN2), between 1 and 5 min, was observed after in vitro incubation of Ehrlich ascites tumor cells at 37°C in phosphate-buffered saline containing HN2 followed by washing in 0°C phosphate-buffered saline. After a second incubation in 37°C phosphate-buffered saline without HN2, the cells lost about one-half of the drug which had been taken up, that which had not been covalently bound to macromolecules.

The basal cytotoxic effect of HN2 on the cells was determined using a standard in vivo test for cell viability. Host survival was measured after 10⁵ HN2-treated cells were injected i.p. into recipient mice, compared with injection of 10⁵ untreated cells into paired control mice. Five min incubation of cells in vitro with multilamellar liposome vesicles (MLV) composed of L()dipalmitoyl-phosphatidyl choline in the presence of HN2, significantly increased tumor cell kill and mouse survival over HN2 alone. In contrast, added Ca²⁺ plus HN2 decreased cytotoxicity and survival. Significant increases in host survival following MLV treatment occurred without significant increase in total HN2 uptake and could be highly correlated with increased amounts of HN2 bound to DNA.

Addition of vincristine (an inhibitor of microtubule polymerization) in the presence of HN2 also decreased the cytotoxic effect of HN2. The vincristine inhibition occurred, without altering total cell HN2 uptake, whether L()dipalmitoyl-phosphatidyl choline MLV were present or not. It is proposed that both Ca²⁺ and MLV act at membrane sites so as to alter the subcellular distribution and localization of HN2 and its accessibility to critical targets. This has been confirmed for MLV by demonstrating increased alkylation of DNA.

¹ To whom requests for reprints should be addressed, at Laboratories of Pharmacology, Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street 6009, Philadelphia, PA 19104.

Received 1/31/86. Revised 5/20/86. Revised 8/11/86. Revised 10/ 8/86. Accepted 10/13/86.