Poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic or """"""""poloxamer"""""""") have been shown to sensitize resistant tumors, resulting in an increase in the cytotoxic activity of anthracyclines by 2 to 3 orders of magnitude. The mechanisms of sensitization are not well understood. The objective of this proposal is to determine the mechanisms through which Pluronic sensitizes the drug resistant cancer cells. Based on preliminary data, the hypothesis being evaluated is that Pluronic causes selective energy depletion in resistant cells, which can affect various drug resistance systems and result in the sensitization of resistant cells. Therefore, by formulating antineoplastic agents with Pluronic, the chemotherapy of resistant tumors could be improved. Using a panel of cell lines, designed to represent the major resistance mechanisms, as in vitro and in vivo tumor models, the specific aims of the proposed studies are to: (1) Characterize the effects of Pluronic block copolymers on ATP levels in resistant and sensitive cells and identify the mechanisms responsible for the energy depletion, (2) Identify drug/Pluronic formulations effective against resistant cancers and determine whether energy depletion induced by Pluronic is responsible for the potentiation of the cytotoxic effects of these drugs in these cells, (3) Determine whether the effects of Pluronic on the energy state of the cell inhibit the functional activity of specific drug resistance mechanisms and whether inhibition of these mechanisms contributes to the potentiated cytotoxic effects in resistant cells (4) Determine what factors are important for the efficient delivery of Pluronic to the tumor cells in vivo and identify mechanisms responsible for enhanced chemotherapy of resistant tumors in animal tumor model.
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