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Metabolic Fate of Liposomal Phosphatidylinositol in Murine Tumor Cells: Implications for the Mechanism of Tumor Cell Cytotoxicity

Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100 [M. J., C. R. A.], and Department of Clinical Biochemistry, Banting Institute, University of Toronto, Toronto, Ontario, Canada MSG 1L5 [J. C., N. Z. S.]

The mechanism of the previously reported cytotoxicity of liposomes containing plant phosphatidylinositol (PI) against numerous tumor cell lines was examined in detail by using liposomes containing synthetic PI specifically labeled either with radioactive myo-inositol, or in the sn-2 position with radioactive linoleic acid, oleic acid, or arachidonic acid. The uptake of liposomal PI by N4TG1 neuroblastoma cells increased with time and was dependent on the nature of the fatty acids. Uptake was highest with liposomal PI containing linoleic acid followed by arachidonic acid and then by oleic acid. The cellular fate of liposomal PI was determined by analysis of radioactive metabolites present in extracts of tumor cell lipids. Appearance of liposomal PI metabolic products in the tumor cells was correlated with thymidine uptake as a measure of viability. After 3 h incubation of cells with PI liposomes it was found that the release of both radioactive liposomal fatty acids (and probably also lyso-PI) and radioactive diglycerides was correlated inversely with the cellular uptake of [methyl-³H]thymidine and uptake of [³H]myoinositol. An experiment in which liposomes were prepared both from animal PI which contained predominantly saturated fatty acids in the sn-2 position and an increasing mole fraction of a synthetic PI containing radioactive linoleic acid in the sn-2 position established that the amount of PI containing linoleic acid in the sn-2 position could be correlated with a decrease in the amount of thymidine uptake by tumor cells. The above results clearly established that phospholipases A₂ and C in the tumor cells were responsible for the formation of metabolites of liposomal PI, and these metabolic products might have been responsible for cytotoxicity and cell death.

¹ To whom reprint requests should be addressed, at Division of Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100.

² N. Z. S. was supported by a United States National Research Council Senior Research Associateship while on sabbatical leave from the University of Toronto. J. C. was supported by the Medical Research Council (Canada).

Received 10/17/84. Revised 5/17/85. Accepted 6/24/85.

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