The drugs are called angiogenesis inhibitors. They block a chemical signal called vascular endothelial growth factor or VEGF. Drugs that block VEGF starve tumors by keeping them from growing new blood vessels.
One such drug is Genentech's Avastin. Ironically, a new generation of more powerful drugs in the same general class -- now under development by several drug companies -- may pose even more danger, says study researcher M. Luisa Iruela-Arispe, MD, professor and vice chairwoman of molecular, cell, and developmental biology at UCLA.
"VEGF contributes to the upkeep and maintenance of the cells that line our blood vessels -- and is made by these cells themselves," Iruela-Arispe tells WebMD. "That was the first surprise from our studies. The second surprise was that we didn't know such a small amount of VEGF was so important. If we don't have it -- well, in mice, more than half die at a young age. It is like sudden death in a 35-year-old person."
Blood vessel cells make only a miniscule amount of VEGF. Most VEGF comes from other places in the body. In their studies, Iruela-Arispe and colleagues genetically engineered mice to have normal VEGF production -- except in their blood vessel cells.
The mice should have had plenty of VEGF to make up for the small amount made by the blood vessel cells, says Charles Francis, MD, director of the hemostasis and thrombosis program at the University of Rochester. Francis was not involved in the study.
"These mice should have been happy, but that was not the case," Francis tells WebMD. "A lot of these mice died as embryos or early in life. The researchers looked into this and showed that the VEGF made in the blood vessel cells is required for their survival."
VEGF Inside Cells
As it turns out, VEGF affects cells in two ways. One way is from the outside. The other way is from the inside. VEGF appears to be one of the very few chemical signals in the body that functions from inside the cell.
"We found this survival signal is occurring inside of the cells," Iruela-Arispe says. "It makes perfect biological sense. The cell needs to respond quickly -- it doesn't have time to say, 'Where is the VEGF?'"
Avastin only affects the VEGF receptors, or switches, on the outside of cells. This means it may not be as potentially harmful as drugs that block the VEGF switches on the inside of cells, Iruela-Arispe says.
"This may be the reason we don't see more frequent dangerous side effects from Avastin," she says. "But about 5% of Avastin patients have blood clots, and many have high blood pressure that we don't yet understand. Newer, smarter drugs go inside the cell and focus on the inside pool of VEGF receptors as well as the outside pool. These will have more side effects than Avastin does."
None of this means cancer patients should avoid VEGF inhibitors.
"If I had an aggressive cancer, I would take these drugs -- even the new ones," Iruela-Arispe says. "If my choice is dying from cancer in six months or taking a risk of a side effect that may never happen, I will certainly take the risk. These are great drugs, but we should continue the search for better ones."
Francis says the message is not that VEGF inhibitors are bad, but that doctors and patients should be aware of the risks.
"If you get into treatments targeting this VEGF pathway, it is going to have to be very carefully done," he says.
Iruela-Arispe and colleagues report their findings in the Aug. 24 issue of the journal Cell.