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
Year: 2003
Type: dissertation
Abstract: Several studies have described the potent anti-tumor activity of RRR-α- \ntocopheryl succinate (vitamin E succinate; VES), a hydrolyzable ester derivative of RRR- \nα-tocopherol (natural vitamin E), demonstrating that VES is a potent growth inhibitor of \na wide variety of epithelial cancer cell types, including breast, prostate, lung, and colon; \nas well as, hematopoietic-lymphoid leukemia and lymphoma cells, in vitro, and exert \nthese effects via induction of apoptosis, inhibition of DNA synthesis, and induction of \ncellular differentiation. Recent studies have demonstrated VES to have anti-tumor and \nanti-metastatic activity in animal xenograft and allograft models when administered \nintraperitoneally (i.p.), but not when delivered orally, suggesting a possible route specific \ntherapeutic potential. In an effort to develop a clinically useful vitamin E-based \nchemotherapeutic agent and to administer it in a clinically-relevant manner, a nonhydrolyzable \nether analog of RRR-α-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R, \n8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-α-tocopheryloxyacetic \nacid or RRR-α-tocopherol ether-linked acetic acid analog; and abbreviated α-TEA) has \nbeen produced. Data reported here are promising in that they show that a novel vitamin \nE analog exhibits the ability to decrease primary tumor burden and reduce lung and \nlymph node metastasis in a rather rapid and aggressive syngeneic tumor model without \nany overt toxic effects when administered by clinically relevant routes; namely, aerosol \nand oral delivery. Increased rates of tumor cell apoptosis and inhibition of cell \nproliferation in tumors of animals treated with α-TEA, imply that the anti-tumor effect is \ndue, at least in part, to analog triggering of tumor cell death and inhibition of cell \nproliferation. The mechanism of how α-TEA reduces lung metastasis in this model \nsystem is unknown and warrants further investigation, but is unlikely due to a decrease in \nangiogenesis. In addition, combinations of this vitamin E derivative with 9-nitrocamptothecin \n(9-NC), a camptothecin derivative used in the treatment of ovarian and \npancreatic cancers, show an enhanced effect on the decrease in tumor burden in this \nmodel.
Author: Karla A. Lawson
Language: English
Subfield: Biochemistry (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1806072442