New research by scientists at Schepens Eye Research Institute may help explain why the anti-cancer drug Avastin, which targets a growth factor responsible for creation of new blood vessels, causes potentially fatal brain inflammation in certain patients. Institute scientists mimicked the drug's activity in mice and found that it damaged the cell lining that prevents fluid from leaking from the ventricle into the brain. The ventricle is the structure in the brain that holds cerebral spinal fluid after it is produced and which is continuous with the spinal cord. The results are currently published online (on February 11th) in The Journal of Experimental Medicine.
"This finding is significant because it may ultimately modify the way we use systemic drugs that block blood vessel growth, and it also suggests that VEGF (vascular endothelial growth factor) plays a more extensive role in the body than we previously thought," says Dr. Patricia D'Amore, senior scientist at Schepens Eye Research Institute and principal investigator of the study.
The cancer drug Avastin (bevacizumab) is used to treat advanced bowel cancer in combination with chemotherapy. By targeting VEGF,
Avastin inhibits the growth of tumors by cutting off their blood supply and thus depriving them of oxygen and other nutrients. In a small percentage of patients, however, Avastin can cause neurological side effects, ranging from headaches and blurry vision to potentially fatal seizures and brain swelling.
D'Amore and her team found that VEGF normally protects the specialized cells that create a seal between the brain and ventricle and thus prevent fluid from leaking into the brain. When VEGF was blocked in mice, these cells were damaged and the animals developed brain lesions. The authors suspect that Avastin's side effects in humans may be caused by a similar phenomenon. Why these symptoms occur in only a few patients is not yet known.
Authors of the study include Arindel S.R. Maharaj*,2,3, Tony E. Walshe*,2,3, Magali Saint-Geniez2,3, Shivalingappa Venkatesha2,4, Angel E. Maldonado2,3, Nathan C. Himes2, Kabir S. Matharu3, S. Ananth Karumanchi2,4 and Patricia A. D'Amore1,2,3
1Departments of Ophthalmology and Pathology, 2Harvard Medical School, 3Schepens Eye Research Institute, 4Center for Vascular Biology, Departments of Medicine, Obstetrics, Gynecology, Surgery and Pathology, Beth Israel Deaconess Medical Center.
Schepens Eye Research Institute is an affiliate of Harvard Medical School and the largest independent eye research institute in the nation.