Novel Vitamin E Analogue Decreases Syngeneic Mouse Mammary Tumor Burden and Reduces Lung Metastasis1
Abstract
A nonhydrolyzable ether analogue of RRR-α-tocopherol, 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 analogue (α-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 α-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 α-TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. α-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 α-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 α-TEA-treated animals, respectively. α-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, α-TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.