研究发现Avastin引起颅内炎症的可能机制

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最近Schepens Eye研究所的科学家们发现了抗癌药物Avastin在一些患者中发生致命性脑部炎症的可能机制。研究结果发表在《实验医学杂志》2月11日网络版。

Avastin（贝伐单抗）是一种抑制肿瘤血管生成的抗癌药物，通过靶向作用于血管内皮生长因子（VEGF）而阻断肿瘤的血液供应、剥夺肿瘤的氧供和其它营养供应，最终抑制肿瘤生长。Avastin常联合化疗用于治疗晚期肠癌。但在少数患者身上，Avastin可导致神经系统不良反应，轻者头痛、视物模糊，重者发生致命的癫痫发作和脑水肿。

研究所的科学家们在小鼠体内模拟Avastin的活性，发现Avastin可破坏一种防止液体从脑室漏入脑组织的内衬细胞。脑室内主要储存生成的脑脊液，并与脊髓相通。正常情况下VEGF可保护在脑组织与脑室之间形成屏障以阻止液体漏入脑组织的内衬细胞。当小鼠体内的VEGF被阻断后，该细胞受损，脑室内液体漏出，动物出现脑组织损害。作者推测，Avastin在人体内的副作用可能由类似的机制引起。但为何这些症状仅发生于少数患者，目前还不得而知。

Schepens Eye研究所的资深科学家、这项研究的主要负责人Patricia D'Amore博士认为， “这项研究结果意义重大，因为它最终可能会改变我们全身使用阻断血管生长的给药方式，并且提示VEGF在体内所起的广泛作用远超出我们的想像。”
Why Anticancer Drug Avastin Causes Potentially Fatal Brain Inflammation In Certain Patients, Study Suggests

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.

\"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.

The results are currently published online (on February 11th) in The Journal of Experimental Medicine.

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

Author affiliations: 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.