There is a pressing need for new classes of antitumor agents with activity against the common solid human tumors, most of which remain refractory to effective chemotherapy. This need argues for novel rationally based approaches to drug development in the future, combined with more appropriate and effective models for evaluating antitumor activity. A fundamental event connected with neoplastic transformation, and one that distinguishes a normal cell from a tumor cell is the inappropriate or faulty expression of growth regulatory genes (oncogenes). A major function of oncogenes is to code for components of intracellular signal transduction pathways that mediate the events between binding growth factors to cell surface receptors and events in the cell nucleus leading to cell proliferation. The constitutive activation of signal transduction pathways appears to be a prime event leading to unrestrained and transformed cell growth. Thus, signal transduction pathways represent a rational and novel biochemical target at which to direct new anticancer drug development, offering the promise of the selective control of cancer cell growth by exploiting a basic biochemical difference between normal and tumor cells. In our studies we will utilize three signal transduction targets as screens for developing new anticancer drugs. They are, inhibition of intracellular Ca2+ signalling (Project 2), modulation of protein kinase C activity (Project 3) and inhibition of protein tyrosine kinase activity (Project 4). Bioassay directed fractionation of extracts of algae, and exotic plants will be used to isolate and identify novel chemical structures acting on these signal transduction targets (Project 1). Analogues of discovered active agents will also be synthesized and tested against the signal transduction targets (Project 1). Agents with activity against the targets will be tested for growth inhibitory activity against a panel of human tumor cell lines growing in the soft agar colony forming assay (Project 5). The panel contains several chemoresistant human solid tumor types including colon carcinoma so that we may be able to detect disease specific activity. Agents active against any of the cell lines will be tested for in vivo antitumor activity against the same cell lines growing as xenografts in nude mice, and against a panel of other human solid tumor xenografts in nude mice. The goal of the study is to identify novel chemical structures with activity against signal transduction pathways that exhibit significant in vivo antitumor appropriate animal models as candidates for further preclinical development and eventual clinical trial in humans as anticancer drugs.
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