MECHANISM OF ACTION OF DIFFERENTIATION AGENTS

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.