Cure rates for solid tumors are discouraging largely due to the lack of effective chemotherapeutic agents. Thus, there is a need for new therapeutic approaches for solid tumors. It has been proposed that one type of new approach may involve agents which induce the differentiation of malignant cels to a more normal phenotype. The mechanism of action of this type of agent is unknown. The identification of the cellular signal(s) for differentiation induced by these agents may allow for development of new anti-cancer agents which would have little effect on normal cells. The primary goal of this project is the characterization of the mechanism of action of planar-polar chemicals and retinoids in the differentiation of malignant mouse embryo fibroblasts utilizing non-transformed parental cels as controls. Previous work has shown that treatment of malignant mouse cells with differentiation agents restores normal growth control response to growth factors and induces alterations in the molecular phenotype of the malignant cells to a molecular phenotype which is similar to that of the untransformed cell. Molecular alterations include changes in radiolabeled cell surface proteins, membrane antigens and phosphoproteins. In addition, treated malignant cells show altered expression of endogenous growth factors.
The specific aims for this project include the purification of growth factors from cells treated with differentiation agents, molecular and biological characterizations of the effects of these factors on treated and untreated cells from the AKR system and sequential analysis of molecular and biological events relative to the time of addition and removal of differentiation agents. These experiments will permit the determination of alterations in molecular phenotype or growth factor expression which are associated as either primary or secondary effects of differentation.
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