The biological and biochemical properties of materials from marine organisms (crude extracts or pure compounds) will be evaluated at the Pharmaceutical Research Institute of Bristol-Myers Squibb. Emphasis will be given to isolatiOn of new chemical entities characterized by a novel mechanism of action, but traditional screening assays will also be used. Materials will be tested in the following primary screening assays: in vitro cytotoxicity, inhibition of ras-raf interaction, ability to convert mutant to wild type p53, inhibition of tyrosine kinase activity and inhibition of HER2/HER4. All these assays are available as highly automated in microtiter format, allowing for a large throughput and rapid evaluation. Additional primary Screens available are: effects on topoisomerase I or II, inhibition or stimulation of tubulin polymerization, interference with ECF receptor and induction of cell differentiation. Lead extracts or pure compounds active in the primary screens will be further evaluated in panels of appropriate tumor cell lines, to confirm the mechanism of action and to investigate possible effects against tumor cell lines resistant to known anticancer agents. Studies to elucidate the mechanism of action will include inhibition of DNA, RNA and protein synthesis in cell cultures in vitro; inhibition of cell progression through mitosis; induction of cellular changes detectable morphologically (micronuclei formation, induction of microtubule bundling); interaction with DNA; DNA cross-linking and DNA breakage. Compounds active in vitro will be tested in vivo against mouse and human tumor cell lines matching those where the compound showed activity in vitro. Water soluble extracts will also be examined for novel marine toxins. This will be followed by gene cloning, expression of the recombinant protein in E. coli. , and use of active recombinant marine product toxins in immunotoxin molecules both in chemical conjugate form and as fusion proteins.
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