EMBARGOED BY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES FOR 5 p.m. EST MONDAY, DEC. 17, 2001
Promising New Target
for Cancer Chemotherapy
Identified by UCSD and Swedish Researchers
Researchers at the University of California, San Diego (UCSD) School of Medicine, in conjunction with colleagues from Lund University in Sweden, have identified in the laboratory a promising new target for cancer chemotherapy that could impact tumor formation and metastasis by inhibiting cell growth. The findings are reported in the December 18 issue of the Proceedings of the National Academy of Sciences (PNAS).
The research team, led by Jeffrey D. Esko, Ph.D., professor of Cellular and Molecular Medicine and associate director of the UCSD Glycobiology Research and Training Center, reports that tumor growth was blocked in vitro and in laboratory mice by interfering with a cell’s ability to supply itself with vital substances called polyamines.
Cells depend on polyamines for growth. Because these substances play an essential role in cell proliferation, two pathways exist to ensure an adequate supply. Cells produce their own internally, and they gather circulating polyamines that come from dietary sources, such as intestinal bacteria, and those excreted by other cells.
In this study, the researchers showed that a cell-surface sugar molecule called heparan sulfate is critical to the cell’s uptake of circulating polyamines. They also showed that if the internal production of polyamines is blocked, through use of a well-known inhibitor drug called DFMO (difluoromethylornithine), the cell continues to proliferate by simply increasing its external gathering function. Finally, using a heparan sulfate inhibitor that decreased the formation of the cell surface sugar molecules, they demonstrated that inhibiting both of the cell’s supply pathways for polyamines resulted in a dramatic reduction in tumor formation in an experimental model of metastasis.
The "wild-type" mouse lungs in the photos and slides are those with normal production of the enzyme polyamine. Tumor growth is shown. When polyamine is blocked - as illustrated in the "mutant" lungs - there was a dramatic reduction in tumor formation and metastasis.
“This paper demonstrates the principle that inhibiting the production of heparan sulfate and blocking the pathway of polyamine formation provides a combination therapy for treating tumors,” said Esko, who is also a member of the Rebecca and John Moores UCSD Cancer Center. “The heparan sulfate inhibitor that we developed worked reasonably well. Now that we’ve proven the principle, we need to develop better inhibitors.”
DFMO is a well-known and well-tolerated drug traditionally used as an anti-parasitic, but is now being studied in clinical trials as a chemopreventive agent in at-risk individuals for a variety of cancers.
In addition to Esko, the research was conducted by first author Mattias Belting, M.D., Ph.D., Lars-Ake Fransson, M.D., Ph.D., and Lo Persson, M.D., Ph.D., Lund University, Sweden; Mark M. Fuster, M.D., UCSD Department of Medicine; and Jillian R. Brown, Ph.D., UCSD Department of Cellular and Molecular Medicine.
The research was funded by grants from International Union Against Cancer, Swedish Cancer Fund, the Tobacco-Related Disease Program at the University of California, and the US National Institutes of Health.
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