The effect and mechanism of the blood-brain barrier-permeabilizing agent,
RMP-7, was investigated in a series of studies employing a rat RG2
glioma model. Changes in uptake of
carboplatin into
brain tumor and various nontumor brain tissue regions was determined using a sophisticated image analysis system. This system permitted quantitative autoradiography to be analyzed simultaneously with overlayed histological images from the same coronal brain section. A wide range of intracarotid doses of
RMP-7 (0.01 to 9.0 micrograms/kg) was shown to significantly increase the permeability of
carboplatin into
tumor tissue and surrounding brain tissue (up to twofold) in a dose-dependent manner. Additionally, substantially greater permeability effects were seen in the
tumor compared to healthy brain. Moreover, a clear topographic profile was observed in nontumor brain tissue, with progressively less uptake observed with increasing distance from the
tumor. The fact that
RMP-7 increased the uptake of
carboplatin into ipsilateral brain tissue outside the
tumor mass has potential implications for treating human
glioma patients, for it is commonly recognized that
tumor cells typically migrate from the
tumor mass into surrounding brain tissue thereby escaping conventional attempts to destroy the malignant cells. To help elucidate the mechanism of RMP-7's permeability effects, the uptake of
carboplatin was also determined under conditions where either the
bradykinin B2 receptor antagonist,
HOE140, or the B1 antagonist, [desArg10]
HOE140, was coadministered with
RMP-7. Results indicate that RMP-7's effects are mediated specifically through
bradykinin B2 receptors. Furthermore, neither
bradykinin antagonist alone affected the uptake of
carboplatin into the leaky
tumor region, suggesting that abnormal elevations in endogenous
bradykinin activity are not likely responsible for the characteristic leaky nature of the
tumor vascular barrier. The combined results from these studies therefore offer new insight into the characteristics of the vascular barriers in normal and
tumor brain tissue and further elucidate the novel permeability effects of
RMP-7. Together, they support its potential use as an adjunctive
therapy for the selective delivery of chemotherapeutic drugs to
brain tumors and possibly other neurodegenerative conditions.