Warning Sign for Cancer Drugs
Drugs That Block Tumor Blood Vessels May Harm Normal Cells
Aug. 23, 2007 - New drugs that cut off the blood supply to growing tumors
may also harm normal blood vessels, mouse studies show.
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