In the present study we have established that the antitumor activity of alpha-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
alpha-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
alpha-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 microM. 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 (
alpha-tocopheryloxybutyric acid). These findings suggest that TS,
alpha-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.