The hypothesis on which this proposal is based is that intracellular signalling pathways mediating the effects of growth factors and oncogenes represent logical target sites at which to direct new anticancer drug development to exploit basic biochemical differences between normal and tumor cells for the treatment of cancer. Because natural products from higher plants and algae provide a potentially rich source of new and novel chemical compounds, we have decided to concentrate our efforts to discover now mechanism based anticancer agents in this area.
The specific aims of the proposal are: 1. To isolate and identify, through bioassay directed fractionation, new compounds with novel chemical structures from higher plants and algae that act on growth factor and oncogene signal transduction pathways, and exhibit in vitro cytotoxicity. 2. To chemically modify existing active compounds such as staurosporine, erbstatin and suramin and newly discovered compounds to improve their selective cytotoxicity and activity against tumor call signal transduction targets. 3. To develop and utilize the following signal transduction targets for identifying potential anticancer agents; a) alterations in intracellular free Ca2+ regulation b) modulation of protein kinase C activity c) inhibition of protein tyrosine kinase activity 4. To conduct, in conjunction with Specific Aim 3) above, selective in vitro cytotoxicity studies using cultured human solid tumor cell lines. 5. Evaluate in vivo antitumor efficacy of active compounds from 4) above in appropriate mouse and human xenograft tumor models.
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