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Increased Accumulation of Drugs in Multidrug-resistant Cells Induced by Liposomes¹

The Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104 USA [L. W., A. M.] and Institut Jean Godinot and UFR de Pharmacie, University of Reims, Reims, France [J-C. J., M-G. A.]

A multidrug-resistant cell such as the human lymphoblastic leukemic cell CEM/VLB₁₀₀ accumulates far less vinblastine (VLB) than its drug-sensitive parent, CEM. When CEM/VLB₁₀₀ cells are exposed to liposomes consisting of the phospholipids cardiolipin, dioleoylphosphatidic acid, or phosphatidylinositol bearing unsaturated fatty acids and then tested for uptake of VLB, accumulation of drug rapidly rises to levels approaching those of CEM cells, which are relatively unaffected by the liposome treatment. The liposomes are not carriers of entrapped drug. Phosphatidylserine, phosphatidylcholine, and phosphatidylethanolamine are inactive, and the addition of cholesterol to liposomes inhibits uptake. Exposure of cells to liposomes does not appear to alter the efflux of drugs. We suggest that the liposomal lipids, introduced into the plasma membranes of CEM/VLB₁₀₀ cells, change their properties so that accumulation of drugs by cells is largely restored. The cytotoxicity of VLB in CEM/VLB₁₀₀ cells is increased approximately 10-fold by cardiolipin liposomes.

¹ This investigation was supported by USPHS Grants CA19130 and CA10815 and American Cancer Society Grant PDP-19H (L. W.).

² To whom requests for reprints should be addressed, at The Wistar Institute of Anatomy and Biology, 3601 Spruce Street, Philadelphia, PA 19104.

Received 3/ 6/92. Accepted 4/16/92.

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