Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis

A nonhydrolyzable ether analogue of RRR-alpha-tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR-alpha-tocopheryloxyacetic acid or RRR-alpha-tocopherol ether-linked acetic acid analogue (alpha-TEA), exhibits antitumor activity in vitro and in vivo...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2003-05, Vol.2 (5), p.437-444
Main Authors: Lawson, Karla A, Anderson, Kristen, Menchaca, Marla, Atkinson, Jeffrey, Sun, LuZhe, Knight, Vernon, Gilbert, Brian E, Conti, Claudio, Sanders, Bob G, Kline, Kimberly
Format: Article
Language:English
Subjects:
Administration, Oral
Aerosols
alpha-Tocopherol - analogs & derivatives
alpha-Tocopherol - therapeutic use
Animals
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Drug Carriers
Female
Humans
In Situ Nick-End Labeling
Liposomes
Lung Neoplasms - drug therapy
Lung Neoplasms - secondary
Mammary Neoplasms, Experimental - drug therapy
Mammary Neoplasms, Experimental - pathology
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Poly(ADP-ribose) Polymerases - metabolism
Tumor Cells, Cultured - transplantation
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Summary:A nonhydrolyzable ether analogue of RRR-alpha-tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR-alpha-tocopheryloxyacetic acid or RRR-alpha-tocopherol ether-linked acetic acid analogue (alpha-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 micro g/ml alpha-TEA for 3 days produced 6, 34, and 50% apoptosis, respectively, and treatment of cells with 10 micro g/ml for 2, 3, 4, and 5 days produced 20, 35, 47, and 58% apoptosis, respectively. A liposomal formulation of alpha-TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. Alpha-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 alpha-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 alpha-TEA-treated animals, respectively. Alpha-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, alpha-TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.
ISSN:1535-7163