Changes in the concentration of intracellular free Ca2+ ([Ca2+]i) caused by the influx of external Ca2+ or by the release of Ca2+ from stores in the endoplasmic reticulum play an important role in mediating the effects of growth factors and oncogenes on cell proliferation. A major function of proto-oncogenes is to code for components of intracellular signal transduction pathways. The inappropriate expression of an oncogene product or its modification through mutation can lead to constitutive activation of an intracellular signal transduction pathway that is thought to be a cause of unrestrained or transformed cell growth. Several oncogenes act through pathways involving changes in [Ca2+]i. [Ca2+]i signalling, thus, represents a novel and attractive target site for developing drugs to selectively block abnormal oncogene expression in transformed cells and offers the promise of the selective control of tumor cell growth. The goal of the project is to isolate and study novel chemical structures that inhibit growth factor and oncogene related Ca2+ signalling in tumor cells. The primary biochemical target used to screen compounds will be the uptake and second messenger mediated release of 45Ca2+ by the endoplasmic reticulum of permeabilized tumor cells. The compounds will be derived from plant extracts by bioassay directed fractionation, and by the chemical modification of known active agents in collaboration with Project 1. Secondary studies will investigate the ability of selected agents to affect [Ca2+]i signalling in intact cells, particularly the integration of [Ca2+]i signalling with the signal transduction pathways studied by Projects 3 and 4. Active agents will be tested for in vitro growth inhibitory activity by Project 5 and in vivo antitumor activity in animal models by Project 6. The ultimate objective of the studies is to develop new classes of antitumor agents for clinical trial in patients.
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