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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19CA067775-01
Application #
3731785
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nam, Sang-Jip; GaudĂȘncio, Susana P; Kauffman, Christopher A et al. (2010) Fijiolides A and B, inhibitors of TNF-alpha-induced NFkappaB activation, from a marine-derived sediment bacterium of the genus Nocardiopsis. J Nat Prod 73:1080-6
West, Lyndon M; Faulkner, D John (2008) Acanthosulfate, a sulfated hydroxyhydroquinone sesterterpenoid from the sponge Acanthodendrilla sp. J Nat Prod 71:269-71
Martin, Glenroy D A; Tan, Lik T; Jensen, Paul R et al. (2007) Marmycins A and B, cytotoxic pentacyclic C-glycosides from a marine sediment-derived actinomycete related to the genus Streptomyces. J Nat Prod 70:1406-9
Thammana, Sudhakararao; Suzuki, Hideharu; Lobkovsky, Emil et al. (2006) Isolation and structure assignment of an iminotetrasaccharide from a cultured filamentous cyanobacterium Anabaena sp. J Nat Prod 69:365-8
Oh, Dong-Chan; Jensen, Paul R; Kauffman, Christopher A et al. (2005) Libertellenones A-D: induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorg Med Chem 13:5267-73
Tan, Ren Xiang; Jensen, Paul R; Williams, Philip G et al. (2004) Isolation and structure assignments of rostratins A-D, cytotoxic disulfides produced by the marine-derived fungus Exserohilum rostratum. J Nat Prod 67:1374-82
Rao, M Rama; Faulkner, D John (2004) Botryllamides E-H, four new tyrosine derivatives from the ascidian Botrylloides tyreum. J Nat Prod 67:1064-6
Konishi, Masataka; Yang, Xuemin; Li, Bo et al. (2004) Highly cytotoxic metabolites from the culture supernatant of the temperate dinoflagellate Protoceratium cf. reticulatum. J Nat Prod 67:1309-13
Davies-Coleman, Michael T; Dzeha, Thomas M; Gray, Christopher A et al. (2003) Isolation of homodolastatin 16, a new cyclic depsipeptide from a Kenyan collection of Lyngbya majuscula. J Nat Prod 66:712-5
Garo, Eliane; Starks, Courtney M; Jensen, Paul R et al. (2003) Trichodermamides A and B, cytotoxic modified dipeptides from the marine-derived fungus Trichoderma virens. J Nat Prod 66:423-6

Showing the most recent 10 out of 21 publications