Angiogenesis inhibitors that block a tumor's development of an independent blood supply have been touted as effective cancer fighters that result in fewer side effects than traditional chemotherapy.
However, a new study by researchers at UCLA's Jonsson Cancer Center showed that one method of blocking blood supply development could result in serious and potentially deadly side effects.
Several newly developed angiogenesis inhibitors work by blocking vascular endothelial growth factor (VEGF), an important signaling protein that spurs growth of new blood vessels. Avastin, an approved angiogenesis inhibitor for colon and lung cancers, inhibits angiogenesis by blocking VEGF signaling from outside of the cell. UCLA researchers wanted to know what happened when VEGF signaling was blocked from within endothelial cells, a mechanism used by some small molecule drugs currently being tested in late phase clinical trials.
The result was unexpected, and sobering. More than half of the mice in the study suffered heart attacks and fatal strokes, while those that remained alive developed serious systemic vascular illness, said Luisa Iruela-Arispe, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology program at UCLA's Jonsson Cancer Center.
The study appears in Aug. 24, 2007 in the prestigious, peer-reviewed journal Cell.
This was an extremely surprising result, said Iruela-Arispe, past president of the North American Vascular Biology Organization and a national expert on angiogenesis.I think this study is cause for some caution in the use of angiogenesis inhibitors in patients for very long periods of time and in particular for use of those inhibitors that block VEGF signaling from inside the cell.
About 5 percent of patients taking Avastin develop blood clot-related side effects, Iruela-Arispe said. But because Avastin was approved only three years ago, it is unclear what side effects may occur when patients remain on the drug for many years, she said.
In the three-year study, Iruela-Arispe created mice that were missing VEGF in the endothelial cells, the cells that line the inside of blood vessels and form an interface between circulating blood and the vessel wall. Endothelial cells line the circulatory system from the heart to the smallest capillary and reduce friction of the flow of blood. Iruela-Arispe and her team didnt expect to see much of an effect because the amount of VEGF made inside endothelial cells was miniscule compared to the levels of VEGF created outside the cells.
However, 55 percent of the mice in the study died by 25 weeks of age, the equivalent of age 30 in humans. The other mice that were followed into old age were very ill.
some side effects have already been identified in people taking angiogenesis inhibitors, Iruela-Arispe said.And theyve been along the lines of what were seeing in the lab.