UNLOCKING THE BLOOD-BRAIN-BARRIER - A ROLE FOR RMP-7 IN BRAIN-TUMOR THERAPY

The effect and mechanism of the blood-brain barrier-permeabilizing age nt, RMP-7, was investigated in a series of studies employing a rat RG2 glioma model, Changes in uptake of carboplatin into brain tumor and v arious nontumor brain tissue regions was determined using a sophistica ted image analysis system. This system permitted quantitative autoradi ography to be analyzed simultaneously with overlayed histological imag es from the same coronal brain section. A wide range of intracarotid d oses of RMP-7 (0.01 to 9.0 mu g/kg) was shown to significantly increas e the permeability of carboplatin into tumor tissue and surrounding br ain tissue (up to twofold) in a dose-dependent manner, Additionally, s ubstantially greater permeability effects were seen in the tumor compa red to healthy brain, Moreover, a clear topographic profile was observ ed in nontumor brain tissue, with progressively less uptake observed w ith increasing distance from the tumor. The fact that RMP-7 increased the uptake of carboplatin into ipsilateral brain tissue outside the tu mor mass has potential implications for treating human glioma patients , for it is commonly recognized that tumor cells typically migrate fro m the tumor mass into surrounding brain tissue thereby escaping conven tional attempts to destroy the malignant cells. To help elucidate the mechanism of RMP-7's permeability effects, the uptake of carboplatin w as also determined under conditions where either the bradykinin B-2 re ceptor antagonist, HOE140, car the B-1 antagonist, [des-Arg(10)]HOE140 , was coadministered with RMP-7. Results indicate that RMP-7's effects are mediated specifically through bradykinin B-2 receptors. Furthermo re, neither bradykinin antagonist alone affected the uptake of carbopl atin into the leaky tumor region, suggesting that abnormal elevations in endogenous bradykinin activity are not likely responsible for the c haracteristic leaky nature of the tumor vascular barrier. The combined results from these studies therefore offer new insight into the chara cteristics of the vascular barriers in normal and tumor brain tissue a nd further elucidate the novel permeability effects of RMP-7. Together , they support its potential use as an adjunctive therapy for the sele ctive delivery of chemotherapeutic drugs to brain tumors and possibly other neurodegenerative conditions. (C) 1996 Academic Press, Inc.