Control of vasogenic edema in a brain tumor model: comparison between dexamethasone and superoxide dismutase.

OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.