Drugs from the Sea: Cloned Gene from Sea Animal May Prove Key in Cancer Drug Development
December 13, 2004;
edited by J. Strax Oct. 27, 2004
Researchers at Scripps Institution of Oceanography at the University of California, San Diego, and their colleagues have taken a significant step forward in developing a new method to produce drug compounds with potential to treat various types of cancer.
In the current issue of the journal Chemistry and Biology, scientists at Scripps, the University of Minnesota and the Life Sciences Institute describe the development of "bryA," a gene that could help solve problems associated with the production of anticancer agents originally discovered in the marine invertebrate Bugula neritina.
"To be able to show that this gene really exists has been the Holy Grail for the last 10 years," said Scripps Professor Margo Haygood, a coauthor of the paper. "his takes us beyond just suspecting that a bacteria might be involved to actually having a gene that looks like the right thing."
The oceans are the source of a large group of unique natural products with medical potential. These are present mainly in creatures without backbones (invertebrates) such as sponges, tunicates, bryozoans, and molluscs.
Several of these compounds (especially the tunicate metabolite ET-743) show pronounced pharmacological activities and are interesting candidates for new drugs primarily in the area of cancer treatment. Other compounds are currently being developed as pain-killers (ziconotide from the mollusc Conus magus) or to treat inflammation.
The marine invertebrate Bugula neritina is of special interest for possible cancer treatments.
Bugula neritina, a brown bryozoan animal with stringy tufts, lives in a symbiotic relationship with bacteria that act as a chemical defense mechanism for the host animal.
In 2001, Haygood and other scientists in her Scripps laboratory found that such bacteria living in Bugula neritina were the source of bryostatins, a family of chemical compounds being closely studied for their potential as anticancer pharmaceuticals in leukemia, lymphoma and several cancers including colon, breast, ovarian and prostate.
One of the main obstacles impeding widespread bryostatin production is lack of a practical and economically viable method of producing the compounds. The bacteria cannot be grown in laboratories. And collecting vast numbers of the animals at sea would be environmentally destructive.
One way of solving this dilemma is to clone the genes involved in natural bryostatin development. In the Chemistry and Biology paper, the researchers describe the process by which they cloned a large complex of genes and singled out bryA, a gene for a catalyst the authors propose is active in bryostatin biosynthesis.
The researchers say it appears that bryA may synthesize a portion of the pharmacologically active component of bryostatin and therefore may be useful in developing clinically useful bryostatin byproducts.
"The isolation of bryA represents a significant step forward in understanding bryostatin biosynthesis and eventually harnessing bry genes to produce bryostatins and derivatives inexpensively and in abundant quantities," the authors say in the paper, one of the first studies that describes such a cloning achievement from a marine symbiont organism.
Haygood and members of her laboratory are now moving the research forward by attempting to use bryA to extract laboratory-developed bryostatin compounds.
Most cancer drugs work by killing rapidly growing cells, in many cases interfering with the body's normal processes. Bryostatin seems to be effective by "flipping a switch" that controls how cells behave in the body. In the case of leukemia, for example, it seems to bring the cells "to their senses" and make them behave like normal blood cells.
The research paper abstract is online:
Hildebrand M, Waggoner LE, Liu H, Sudek S, Allen S, Anderson C, Sherman DH, Haygood M. bryA; An Unusual Modular Polyketide Synthase Gene from the Uncultivated Bacterial Symbiont of the Marine Bryozoan Bugula neritina.
Chem Biol. 2004 Nov;11(11):1543-52.
Related work:
Davidson SK, Allen SW, Lim GE, Anderson CM, Haygood MG. Evidence for the biosynthesis of bryostatins by the bacterial symbiont "Candidatus Endobugula sertula" of the bryozoan Bugula neritina. Appl Environ Microbiol. 2001 Oct;67(10):4531-7. Free full text
The research was supported by the National Institutes of Health and the Department of Defense.
Scripps Institution of Oceanography, at the University of California, San Diego, is one of the oldest, largest, and most important centers for global science research and graduate training in the world. Hundreds of research programs covering a wide range of scientific areas are under way today in 65 countries. The institution has a staff of about 1,300, and annual expenditures of approximately $140 million from federal, state, and private sources. Scripps operates one of the largest U.S. academic fleets with four oceanographic research ships and one research platform for worldwide exploration.
This page reported by J. Strax, last updated December 13, 2004
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In numerous hematological and solid tumor cell lines, bryostatin-1 inhibits proliferation, induces differentiation, and promotes apoptosis. Furthermore, preclinical studies indicate that bryostatin-1 potently enhances the effect of chemotherapy. In many cases, this effect is sequence specific. Bryostatin-1 is currently in phase I and phase II clinical trials. The major toxicities are myalgias [muscle pains], nausea, and vomiting. Although there is minimal single-agent activity, combinations with standard chemotherapy are providing very encouraging results and indicate a new direction in cancer therapy. 
