July 16, 2004 A drug derived from an ocean-growing sponge teams up to enhance the performance of the yew tree derivative Taxol® (paclitaxel) in preventing the growth of cancer cells, according to research published in the July 15 issue of the journal Cancer Research.
Indeed, discodermolide, a novel drug isolated from the marine sponge Discodermia dissoluta, works with paclitaxel to thwart tumor cell growth--with several times the efficacy that either drug alone exerts on proliferating cancer cells.
Studies by Mary Ann Jordan, Ph.D., a scientist at the University of California, Santa Barbara, and an international team of cancer researchers including postdoctoral fellows Stephane Honore, Ph.D., and Kathryn Kamath, Ph.D., demonstrate that the combination of the two drugs inhibited proliferation of human lung cancer cells by 41 percent. Administered alone, either discodermolide or paclitaxel prevented the cancer cell growth by only 9.6 or 16 percent, respectively. The drugs also combined to induce programmed cell death, or apoptosis, in the lung cancer cells.
"Our results indicate that Taxol® and discodermolide have the potential to improve cancer patients' responses and reduce undesirable side effects when the two drugs are administered together," Jordan said.
The drugs, which stem from naturally occurring sources, work in concert to stabilize the assembly/disassembly process of microtubules in cells. Microtubules--lengthy polymers made up of protein bundles, called tubulin--form long, straw-like cylinders that help shape the skeletal structure within cells and also move cellular components within the cell, including vesicles, granules, organelles like mitochondria, and chromosomes. Their attachment with chromosomes, the DNA genetic material in cells, is critical for cell replication and growth. Microtubules normally exist in a state of dynamic instability, where the polymers grow rapidly--longer or shorter, depending on the need of the cells.
In this study, discodermolide and paclitaxel combined to alter the overall microtubule dynamics by 71 percent when administered together. Alone, they each reduced microtubule dynamic instability by 24 percent.
By altering the stability dynamics of microtubules, paclitaxel and discodermolide limit cancer cells ability to duplicate DNA and divide. The cells are stuck in a pre-division stage of the cell cycle called G2/M. Cancer cells that are restricted to the pre-division stage of the cell cycle cannot divide and ultimately die, thus reducing proliferation of tumor cells.
Both drugs work by binding to the microtubules. Because of their lengthy structure and the number of drug binding sites normally associated with them, microtubules are unique receptors for drugs within cells.
Paclitaxel is currently an approved therapeutic for control of cancer growth. Discodermolide is currently under study in phase one clinical studies.
Jordan is an adjunct professor and research biologist in the Molecular, Cellular, and Developmental Biology department, University of California, Santa Barbara. In the paclitaxel/discodermolide studies, she collaborated with researchers from the Universite de la Mediterranee, Marseille, France; Albert Einstein College of Medicine, Bronx, N.Y.; and the University of California, Santa Barbara, Calif. The work was supported by grants from the National Institutes of Health.
Founded in 1907, the American Association for Cancer Research is a professional society of more than 22,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR's Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.
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