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 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.
Lawson
Karla A
KA
Division of Nutrition/A2703, University of Texas at Austin, Austin, Texas 78712-1097, USA.
Anderson
Kristen
K
Menchaca
Marla
M
Atkinson
Jeffrey
J
Sun
LuZhe
L
Knight
Vernon
V
Gilbert
Brian E
BE
Conti
Claudio
C
Sanders
Bob G
BG
Kline
Kimberly
K
D000284:Administration, Oral; D000336:Aerosols; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004337:Drug Carriers; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000336:Aerosols; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011065:Poly(ADP-ribose) Polymerases; D024502:alpha-Tocopherol