Investigation of the effect of a novel vitamin E derivative (alpha-TEA) alone and in combination with a known chemotherapuetic agent in human breast cancer using cell culture and animal models
textSeveral studies have described the potent anti-tumor activity of RRR-α-
tocopheryl succinate (vitamin E succinate; VES), a hydrolyzable ester derivative of RRR-
α-tocopherol (natural vitamin E), demonstrating that VES is a potent growth inhibitor of
a wide variety of epithelial cancer cell types, including breast, prostate, lung, and colon;
as well as, hematopoietic-lymphoid leukemia and lymphoma cells, in vitro, and exert
these effects via induction of apoptosis, inhibition of DNA synthesis, and induction of
cellular differentiation. Recent studies have demonstrated VES to have anti-tumor and
anti-metastatic activity in animal xenograft and allograft models when administered
intraperitoneally (i.p.), but not when delivered orally, suggesting a possible route specific
therapeutic potential. In an effort to develop a clinically useful vitamin E-based
chemotherapeutic agent and to administer it in a clinically-relevant manner, a nonhydrolyzable
ether analog of RRR-α-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R,
8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-α-tocopheryloxyacetic
acid or RRR-α-tocopherol ether-linked acetic acid analog; and abbreviated α-TEA) has
been produced. Data reported here are promising in that they show that a novel vitamin
E analog exhibits the ability to decrease primary tumor burden and reduce lung and
lymph node metastasis in a rather rapid and aggressive syngeneic tumor model without
any overt toxic effects when administered by clinically relevant routes; namely, aerosol
and oral delivery. Increased rates of tumor cell apoptosis and inhibition of cell
proliferation in tumors of animals treated with α-TEA, imply that the anti-tumor effect is
due, at least in part, to analog triggering of tumor cell death and inhibition of cell
proliferation. The mechanism of how α-TEA reduces lung metastasis in this model
system is unknown and warrants further investigation, but is unlikely due to a decrease in
angiogenesis. In addition, combinations of this vitamin E derivative with 9-nitrocamptothecin
(9-NC), a camptothecin derivative used in the treatment of ovarian and
pancreatic cancers, show an enhanced effect on the decrease in tumor burden in this
model.Nutritional Science
