Target for cancer chemotherapy

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 target for cancer chemotherapy that could impact tumour formation and metastasis by inhibiting cell growth.

The research team led by Jeffrey Esko, professor of Cellular and Molecular Medicine, reports that tumour 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 an inhibitor drug (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 tumour formation in an experimental model of 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 tumours," said Esko. "The heparan sulfate inhibitor that we developed worked reasonably well. Now that we have proven the principle, we need to develop better inhibitors."

Difluoromethylornithine 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.