Unlocking the blood-brain barrier: a role for RMP-7 in brain tumor therapy.
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.
Elliott
P J
PJ
Alkermes, Inc., Cambridge, Massachusetts 02139, USA.
Hayward
N J
NJ
Huff
M R
MR
Nagle
T L
TL
Black
K L
KL
Bartus
R T
RT
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016190:Carboplatin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D007700:Kinetics; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin