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 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.
Fariss
M W
MW
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0662.
Fortuna
M B
MB
Everett
C K
CK
Smith
J D
JD
Trent
D F
DF
Djuric
Z
Z
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002788:Cholesterol Esters / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006098:Granulocytes / Q000166:cytology*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D024505:Tocopherols; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D002087:Butyrates; D002788:Cholesterol Esters; D020148:Butyric Acid; D014810:Vitamin E; D004317:Doxorubicin; D024505:Tocopherols; C013440:cholesteryl succinate