Browsing by Subject "Vitamin E--Derivatives--Analysis"
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Item 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(2003) Lawson, Karla Ann; Kline, Kimberly; Sanders, Bob G.Several 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.Item Investigation of the effects and mechanisms of action of a novel vitamin E derivative (alpha-TEA) in combination with Cisplatin, and the resulting reversal of drug resistance in a Cisplatin-resistant human ovarian cancer cell line, Cp70(2003-05) Anderson, Kristen Marie; Kline, Kimberly; Sanders, Bob G.RRR-α-tocopheryl succinate (VES) and vitamin E analog [2,5,7,8-tetramethyl- 2R-(4R,8R-12-trimethyltridecyl)chroman-6-yloxy] acetic acid (α-TEA) induce human breast, prostate, lung, colon, cervical, and endometrial tumor cells in culture to undergo apoptosis. An exception is the human ovarian cancer cell line A2780, and its cisplatin- resistant subclone A2780/cp70 (cp70). These cells are responsive to the induction of apoptosis by α-TEA, but not VES. Evidence in these studies indicate that differences in the structural integrity (stability) of the ester linked succinate moiety of VES versus the ether linked acetic acid moiety of α-TEA explains, in part, why cp70 cells respond differently to the induction of apoptosis by the two compounds. Data suggest that the failure of VES to induce cp70 cells to undergo apoptosis is due to cellular esterases that convert VES to RRR-α-tocopherol, removing its anti-tumor activity. The ether linkage of α-TEA is not hydrolysed in these cells. Thus, due to its stability, the α-TEA molecule shows more promise not only in these cell lines in culture, but also as a more clinically relevant chemotherapeutic agent. In addition, combination treatments of α-TEA with cisplatin induced high levels of apoptosis in both A2780 and cisplatin-resistant cp70 cells. Evidence indicates a synergistic relationship between these two compounds in this ovarian cancer cell line, as α-TEA restores signaling through MAP kinase pathways that have been lost in the acquisition of cisplatin resistance. Preliminary in vivo data support these in vitro results confirming the efficacy of combination therapy. Co-treatment of α-TEA administered via aerosol with cisplatin treatment via intraperitoneal injection reduces tumor burden and metastasis to lungs and lymph nodes in a nude mouse xenograft model of the cp70 cisplatin-resistant cell line.