Goals are to understand how the vitamin E derivative, RRR-alpha-tocopheryl succinate (vitamin E succinate; VES) inhibits retrovirus-transformed tumor cell proliferation in vitro, and to determine if RRR-alpha-tocopheryl polyethylene glycol 1000 succinate (VES attached to polyethylene glycol 1000; TPGS) will serve as an effective therapeutic agent for preventing cachexia (weight loss, severe generalized immune suppression and anemia) and fatal lymphoid leukosis in animals challenged with retrovirus- transformed tumor cells or infectious retrovirus. The studies will be conducted with avian reticuloendotheliosis virus (REV-T/REV-A), and REV- transformed RECC-UTC4-1 lymphoblastoid cells; both are tumorigenic, induce cachexia and lethal reticuloendotheliosis when injected into histocompatible chickens. The in vitro studies will determine if cell cycle blockage by VES is caused by induction of antiproliferative transforming growth factor-beta (TGF-betas) which inhibit the phosphorylation of the cell cycle regulatory retinoblastoma gene protein, Rb. The in vivo studies will examine the potential therapeutic efficacy of TPGS in young chickens challenged with either transformed tumor cells (metastasis) or infectious retrovirus (retrovial replication and in vivo transformation). These studies will increase basic knowledge about the antiproliferative properties of VES as well as the TGF-betas, and will characterize TPGS's therapeutic value as an anti-cancer agent and immune modulator. Specific objectives are:
Specific Aim I. Compare the cell cycle blocks created by treatment of RECC-UTC-1 cells with VES, VES-induced TGF-betas, VES-induced low molecular weight antiproliferative factor, as well as purified TGF-betas; and determine if hypophosphorylation of Rb occurs.
Specific Aim II. Characterize athe connection between VES antiproliferative actions and the TGF-beta system.
Specific Aim III. Determine the efficacy of TPGS as a dietary therapeutic agent by conducting in vivo analyses of immune status and general health of chickens inoculated with either RECC-UTC4-1 tumor cells or infectious REV- T/REV-A virus.
