THE SELECTIVE ANTIPROLIFERATIVE EFFECTS OF ALPHA-TOCOPHERYL HEMISUCCINATE AND CHOLESTERYL HEMISUCCINATE ON MURINE LEUKEMIA-CELLS RESULT FROM THE ACTION OF THE INTACT COMPOUNDS

In the present study we have established that the antitumor activity o f alpha-tocopheryl succinate (TS, vitamin E succinate) and cholesteryl succinate (CS) result from the action of the intact TS and CS compoun ds and not from the release of alpha-tocopherol, cholesterol, or succi nate. We report that treatment of murine leukemia cell lines C1498 (my eloid) and L1210 (lymphocytic), with the tris salts of TS or CS, but n ot alpha-tocopherol and tris succinate or cholesterol and tris succina te, significantly inhibit the growth of these tumor cells and signific antly 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-gr anulocyte-macrophage). In fact, colony-forming unit granulocyte macrop hage cell growth was stimulated by exposure to CS and TS (as well as t heir ether analogues) at concentrations above 100 mu M. Furthermore, p retreatment of colony-forming unit granulocyte-macrophage cells with T S or CS appears to protect these normal cells from the lethal effect o f doxorubicin exposure. Selective inhibition of leukemia cell prolifer ation (identical to that noted for CS and TS) was also observed follow ing 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 selectiv e antitumor agents when administered alone or in combination with doxo rubicin by a route that ensures tissue accumulation of the intact comp ound.