Shoshan Y, Siegal T
Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel.
Neurosurgery. 1996 Dec;39(6):1206-13; discussion 1213-4. doi: 10.1097/00006123-199612000-00025.
The production of prostaglandin (PG) within brain tumors probably generates excessive amounts of oxygen free radicals that may disrupt microvessel permeability within the tumor and in the adjacent brain. We evaluated the effect of systemic therapy with recombinant human manganese-superoxide dismutase (r-hMnSOD) and with dexamethasone on the vascular permeability (VP) of a brain tumor and the adjacent brain. Treatment effect was also evaluated in control animals subjected to mild penetration injury.
Fischer rats were injected stereotactically with either 10(5) cells of malignant sarcoma or with vehicle into the right parietal hemisphere. Nine days later, the animals were treated with r-hMnSOD (50 mg/kg of body weight every 12 h [one intravenous, then two intraperitoneal injections]; serum levels, 1100-1800 micrograms/ml), dexamethasone (2 mg/kg every 12 h [one intravenous, then two intraperitoneal injections]), or vehicle and were killed after 30 hours for evaluation of VP and PG production.
The VP was markedly increased within the tumor (P < 0.001), in the brain adjacent to it, and in the vehicle injection site. The VP of the normal brain was unaffected by r-hMnSOD or dexamethasone treatment, unlike the VP in the tumor, the adjacent brain, and the injection sites of control animals, where it was reduced by 50, 54, and 23%, respectively (P < 0.04), for r-hMnSOD and 50, 41, and 71%, respectively (P < 0.05), for dexamethasone. A one- to threefold increase in synthesis of thromboxane and PGE2 was measured within the tumor, the adjacent brain, and the injection sites of control animals (P < 0.0001). Treatment with r-hMnSOD had no effect on tumor PG production, but it reduced the synthesis in the brain tissue adjacent to the tumor and in traumatized control animals (P < 0.04). Immunohistochemical evaluation revealed vascular proliferation with abnormal basal membrane, atypical astrocytes, and large numbers of reactive macrophages present in the adjacent brain and at the injection sites of control animals but not within the tumor mass.
Oxygen free radicals probably enhance vasogenic brain edema resulting from tumor and penetration injury. The edema can be attenuated by systemic r-hMnSOD therapy, which has been proven to be as effective as steroid treatment. An inflammatory response may account for oxygen free radical production in brain tissue adjacent to the tumor and at the injection site of vehicle solution, but other mechanisms probably generate oxygen free radicals within the tumor mass.
脑肿瘤内前列腺素（PG）的产生可能会生成过量的氧自由基，这些自由基可能会破坏肿瘤内部及邻近脑组织中的微血管通透性。我们评估了重组人锰超氧化物歧化酶（r-hMnSOD）和地塞米松全身治疗对脑肿瘤及邻近脑组织血管通透性（VP）的影响。还对遭受轻度穿透伤的对照动物的治疗效果进行了评估。
将Fischer大鼠立体定向注射到右顶叶半球，注射的要么是10⁵个恶性肉瘤细胞，要么是赋形剂。9天后，用r-hMnSOD（每12小时50mg/kg体重[一次静脉注射，然后两次腹腔注射]；血清水平为1100 - 1800μg/ml）、地塞米松（每12小时2mg/kg[一次静脉注射，然后两次腹腔注射]）或赋形剂治疗动物，30小时后处死以评估VP和PG产生情况。
肿瘤内部、其邻近脑组织以及赋形剂注射部位的VP均显著增加（P < 0.001）。正常脑组织的VP不受r-hMnSOD或地塞米松治疗的影响，与肿瘤、邻近脑组织以及对照动物注射部位的VP不同，在这些部位，r-hMnSOD治疗后VP分别降低了50%、54%和23%（P < 0.04），地塞米松治疗后VP分别降低了50%、41%和71%（P < 0.05）。在肿瘤、邻近脑组织以及对照动物注射部位，血栓素和PGE2的合成增加了1至3倍（P < 0.0001）。r-hMnSOD治疗对肿瘤PG产生没有影响，但它降低了肿瘤邻近脑组织和创伤对照动物脑组织中的合成（P < 0.04）。免疫组织化学评估显示，在邻近脑组织和对照动物注射部位存在血管增殖，伴有基底膜异常、非典型星形胶质细胞和大量反应性巨噬细胞，但肿瘤块内未见。
氧自由基可能会加重肿瘤和穿透伤导致的血管源性脑水肿。全身r-hMnSOD治疗可减轻水肿，已证明其与类固醇治疗一样有效。炎症反应可能是肿瘤邻近脑组织和赋形剂溶液注射部位氧自由基产生的原因，但肿瘤块内氧自由基的产生可能还有其他机制。
