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The Selective Antiproliferative Effects of -Tocopheryl Hemisuccinate and Cholesteryl Hemisuccinate on Murine Leukemia Cells Result from the Action of the Intact Compounds¹

Environmental and Molecular Taxicology Laboratory, Department of Pathology [M. W. F.], Medical Chemistry [J. D. S.], and Internal Medicine [D. F. T.], Division of Hematology and Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0662; and Department of Internal Medicine, Division of Hematology and Oncology, Wayne State University, School of Medicine, Detroit, Michigan 48202-0188 [M. B. F., C. K. E., Z. D.]

In the present study we have established that the antitumor activity of -tocopheryl succinate (TS, vitamin E succinate) and cholesteryl succinate (CS) result from the action of the intact TS and CS compounds and not from the release of -tocopherol, cholesterol, or succinate. We report that treatment of murine leukemia cell lines C1498 (myeloid) and L1210 (lymphocytic), with the tris salts of TS or CS, but not -tocopherol and tris succinate or cholesterol and tris succinate, significantly inhibit the growth of these tumor cells and significantly enhance doxorubicin-induced tumor cell kill in a similar fashion. In contrast, the treatments mentioned above did not adversely affect the growth of murine normal bone marrow cells (colony-forming unit-granulocyte-macrophage). In fact, colony-forming unit granulocyte-macrophage cell growth was stimulated by exposure to CS and TS (as well as their ether analogues) at concentrations above 100 µM. Furthermore, pretreatment of colony-forming unit granulocyte-macrophage cells with TS or CS appears to protect these normal cells from the lethal effect of doxorubicin exposure. Selective inhibition of leukemia cell proliferation (identical to that noted for CS and TS) was also observed following the treatment of cells with the nonhydrolyzable ether forms of CS (cholesteryloxybutyric acid) and TS (-tocopheryloxybutyric acid). These findings suggest that TS, -tocopheryloxybutyric acid, CS, and cholesteryloxybutyric acid may prove clinically useful as selective antitumor agents when administered alone or in combination with doxorubicin by a route that ensures tissue accumulation of the intact compound.

¹ This research is dedicated to Doris Wise Fariss and is supported by National Institute of Evironmental Health Sciences Grant R01 ES05452 (M. W. F.) and the Wayne State University Ben Kasle Trust Fund for Cancer Research.

² To whom requests for reprints should be addressed, at Department of Pathology, Box 980662, MCV/VCU, Richmond, VA 23298.

Received 2/28/94. Accepted 5/16/94.

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