Liposomal Formulated-dl-alpha Tocopherol :Mammary Tumor

#C164 Liposomal Formulated dl-alpha-Tocopherol Acetate Administered by Aerosol or Gavage Reduce Syngeneic Mouse Mammary Tumor Burden and Metastasis.

Weiping Yu, Li Jia, Bob G. Sanders, Kimberly Kline,

Univ. of Texas, Austin, TX.

Synthetic vitamin E, dl-alpha-tocopherol, and its derivative dl-alpha-tocopherol acetate, commonly used as dietary supplements, are ineffective in preventing tumor cell growth in culture, and show inconsistent results when used as chemopreventive agents in chemically-induced mammary cancer in rats.

In this paper, we compare the antitumor properties of liposomal formulations of these two forms of vitamin E to alpha-TEA, a novel vitamin E analog with established anti-cancer properties in vitro, and in vivo (Kawson, K.A., et al. Mol. Cancer Therap. 2:437-44, 2003).

In comparison to alpha-TEA, the two synthetic vitamin E forms are ineffective in preventing growth of human breast cancer cells or Balb/c 66cl-4-GFP mammary cancer cells in vitro.

However, liposomal formulated dl-alpha-tocopherol and dl-alpha-tocoperol acetate administered by aerosol or orally by gavage to Balb/c mice transplanted with 66cl-4-GFP tumor cells significantly inhibited tumor burden and lung and lymph node metastasis in a manner similar to alpha-TEA.

Liposomal formulated dl-alpha-tocopherol or dl-alpha-tocopherol acetate delivered by aerosol or gavatge reduced tumor volume by 65 and 33% and by 56 and 38%, respectively.

Visible lung metastases were reduced by 82 and 46% when dl-alpha-tocopherol and dl-alpha-tocopherol acetate were administered by aerosol and 100 and 57% when administered by gavage.

Liposomal formulated dl-alpha-tocopherol acetate administered by gavage reduced lung micrometastases by 77 and 70% and reduced lymph nod metastases by 64% and 57%, respectively.

Immunohistological analyses of tumor sections from dl-alpha-tocopherol or dl-alpha-tocopherol acetate treated mice each showed a 53% reduction of expression of endothelial antigen CD31, an indicator of small capillaries in primary tumor tissue.

alpha-TEA showed a 60% reduction of CD31 staining.

Analyses of tumor sections from dl-alpha-tocopherol and dl-alpha-tocopherol acetate gavage treated mice by TUNEL for apoptosis and Ki-67 staining for cell proliferation showed 387 and 32% enhanced apoptosis and 39 and 25% reduction in Ki-67, respectively.

Tumor sections from alpha-TEA treated mice showed 44% increase in apoptosis and 39% decrease in cell proliferation. Based on these data, we conclude that dl-alpha-tocopherol and dl-alpha-tocopherol acetate inhibition of tumor growth is similar to alpha-TEA.

In contrast to dl-alpha-tocopherol and dl-alpha-tocopherol acetate, RRR-alpha-tocopherol, a naturally occurring form of tocopherol, shows little to no anti-tumor activity in the 66cl-4-GFP tumor model when formualted in lipsomes and administered by aerosol or gavage.

Since the dl-form of vitamin E is composed of 8 steroisomers with RRR-alpha-tocopherol representing 1/8 of the forms, these data suggest that dl-alpha-tocopherol stereoisomers other than RRR-alpha-tocopherol are involved in the antitumor activity of these two compounds.

Supported by CA59739 and the Foundations for Research.

Frontiers in Cancer Prevention Research, 2203 AACR

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