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Division of Nutrition/A2703 [K. A. L., K. K.] and School of Biological Sciences/C0900 [K. A., M. M., B. G. S.] University of Texas at Austin, Austin, Texas 78712; Department of Chemistry, Brock University, St. Catharines, Ontario, L2S 3A1 Canada [J. A.]; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 [L. Z. S.]; Department of Molecular Physiology and Biophysics [V. K.] and Department of Molecular Virology and Microbiology [B. E. G.], Baylor College of Medicine, Houston, Texas 77030; and University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 [C. C.]

² To whom requests for reprints should be addressed, at Division of Nutrition/A2703, University of Texas at Austin, Austin, TX 78712-1097. Phone: (512) 471-8911; Fax: (512) 232-7040; E-mail: k.kline{at}mail.utexas.edu

A nonhydrolyzable ether analogue of RRR--tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR--tocopheryloxyacetic acid or RRR--tocopherol ether-linked acetic acid analogue (-TEA), exhibits antitumor activity in vitro and in vivo using a syngeneic BALB/c mouse mammary tumor model (line 66 clone 4 stably transfected with green fluorescent protein). Treatment of cells with 5, 10, and 20 µg/ml -TEA for 3 days produced 6, 34, and 50% apoptosis, respectively, and treatment of cells with 10 µg/ml for 2, 3, 4, and 5 days produced 20, 35, 47, and 58% apoptosis, respectively. A liposomal formulation of -TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. -TEA-treated animals showed a significant decrease in tumor volumes over 17 days of aerosol treatment (P < 0.001). Forty percent of aerosol as well as untreated control mice had visible, macroscopic lung metastases versus none (0%) of the -TEA-treated mice. On the basis of fluorescence microscopic examination of the surface (top and bottom) of flattened whole left lung lobes, an average of 60 ± 15 and 102 ± 17 versus 11 ± 4 fluorescent microscopic metastases was observed in aerosol control and untreated control versus -TEA-treated animals, respectively. -TEA formulated in ethanol + peanut oil (5 mg/mouse/day) delivered by gavage did not reduce s.c. primary tumor burden; however, fluorescent microscopic lung metastases were significantly reduced (P < 0.0021). In summary, -TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.

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