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ORIGINAL RESEARCH ARTICLE

Comparison of Vitamin E Derivatives -TEA and VES in Reduction of Mouse Mammary Tumor Burden and Metastasis

Karla A. Lawson^*,1, Kristen Anderson^*,2, Marla Simmons-Menchaca^*, Jeffrey Atkinson, LuZhe Sun, Bob G. Sanders^* and Kimberly Kline^*,3

^* Division of Nutrition and School of Biological Sciences, University of Texas, Austin, Texas 78712 Department of Chemistry, Brock University, St. Catharines Ontario, Canada; and Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229

To whom requests for reprints should be addressed at ³ Division of Nutrition/A2703, University of Texas at Austin, Austin, TX 78712–1097. E-mail: k.kline{at}mail.utexas.edu

A novel nonhydrolyzable ether derivative of RRR--tocopherol, RRR--tocopherol ether acetic acid analog [2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (-TEA)], and a hydrolyzable ester derivative RRR--tocopheryl succinate (vitamin E succinate; VES) inhibited BALB/c mouse 66cl-4-GFP mammary tumor cell growth in vitro and in vivo. Treatment of 66cl-4-GFP cells in culture with -TEA or VES induced dose-dependent DNA synthesis arrest and apoptosis and inhibited colony formation. Liposomal formulations of -TEA delivered orally or by aerosol significantly reduced subcutaneous 66cl-4-GFP tumor burden and metastasis to lung and lymph nodes. Liposomal formulations of VES delivered by aerosol significantly reduced tumor burden and lung metastasis, but not lymph node metastasis. Unlike -TEA, VES was ineffective in reducing tumor burden and metastasis to lungs and lymph nodes when administered orally. Analyses of tumor sections showed that -TEA delivered by either method significantly reduced tumor cell proliferation as measured by Ki67, and increased apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), whereas VES delivered by aerosol reduced tumor cell proliferation and increased apoptosis, but not significantly. In summary, the nonhydrolyzable ether vitamin E derivative -TEA was effective in reducing tumor burden and metastasis when delivered either by aerosol or orally, whereas the hydrolyzable ester vitamin E derivative VES was effective only when delivered by aerosol.

Key Words: vitamin E analog -TEA • RRR--tocopheryl succinate (VES) • metastasis • antitumor agents • syngeneic mouse mammary cancer model

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