rmp-7 and Glioma

Labradimil (Cereport; also formerly referred to as RMP-7) is a 9-amino-acid peptide designed for selectivity for the bradykinin B2 receptor and a longer plasma half-life than bradykinin. It has been developed to increase the permeability of the blood-brain barrier (BBB) and is the first compound with selective bradykinin B2 receptor agonist properties to progress from concept design through to tests of efficacy in patients. In vitro studies demonstrate that labradimil has a longer half-life than bradykinin and selectively binds to bradykinin B2 receptors, initiating typical bradykinin-like second messenger systems, including increases in intracellular calcium and phosphatidylinositol turnover. Initial proof of principle studies using electron microscopy demonstrated that intravenous labradimil increases the permeability of the BBB by disengaging the tight junctions of the endothelial cells that comprise the BBB. Autoradiographic studies in rat models further demonstrated that labradimil increases the permeability of the BBB in gliomas. Intravenous or intra-arterial labradimil increases the uptake of many different radiolabelled tracers and chemotherapeutic agents into the tumour in a dose-related fashion. These effects are selective for the tumour and for the brain surrounding the tumour, and are particularly robust in tumour areas that are normally relatively impermeable. The increased chemotherapeutic concentrations are maintained for at least 90 minutes, well beyond the transient effects on the BBB. The increase in permeability with labradimil occurs rapidly but is transient, in that restoration of the BBB occurs very rapidly (2 to 5 minutes) following cessation of infusion. Even with continuous infusion of labradimil, spontaneous restoration of the barrier begins to occur within 10 to 20 minutes. Collectively, these data demonstrate that the B2 receptor system that modulates permeability of the BBB is highly sensitive and autoregulated and that careful attention to the timing of labradimil and the chemotherapeutic agent is important to achieve maximal effects. Survival studies in rodent models of both gliomas and metastatic tumours in the brain demonstrate that the enhanced uptake observed with the combination of labradimil and water-soluble chemotherapeutics enhances survival to a greater extent than achieved with chemotherapy alone. Finally, preliminary clinical trials in patients with gliomas provide confirmatory evidence that labradimil permeabili

Topics: Animals; Blood-Brain Barrier; Bradykinin; Capillary Permeability; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Glioma; Half-Life; Humans; Rats; Receptor, Bradykinin B2; Receptors, Bradykinin

Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to potentially improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing. However, delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The goal of the current Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy.. RMP-7 was given before the end of carboplatin infusion. Local radiotherapy (5940 centigrays) was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion, in cohorts of 3, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, whose median age was 7 years (range, 3-14 yrs).. One child died early in treatment of progressive disease and was not assessable for toxicity. Treatment for 3, 4, or 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. Of 3 children treated at the full duration of therapy (33 doses over 7 wks), 1 developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival period was 328 days, and 1 patient remained disease progression free > 400 days from initiation of treatment.. The results of the current study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bradykinin; Brain Stem Neoplasms; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Glioma; Humans

Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas.. RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3-12 yrs).. One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment.. The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bradykinin; Brain Stem Neoplasms; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Feasibility Studies; Female; Glioma; Humans; Male; Radiotherapy; Radiotherapy Dosage; Survival Rate; Treatment Outcome

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bradykinin; Carboplatin; Confidence Intervals; Double-Blind Method; Female; Glioblastoma; Glioma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Survival Rate

Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood-brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials.. Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100-300 ng/ kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls.. Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration time curve (AUC) of 7 mg/ml x min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104-133% of target, Spearman rank correlation coefficient = 0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106-189% of target).. Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Astrocytoma; Blood Proteins; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carboplatin; Female; Glioblastoma; Glioma; Half-Life; Humans; Male; Middle Aged; Protein Binding

The selective bradykinin analogue, RMP-7, transiently increases the permeability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. In 87 recurrent glioma patients (WHO Grade III/IV, median age 46, Karnofsky 70%) clinical and Magnetic Resonance Imaging (MRI) responses to i.v. cycles (q 28 days) of RMP-7 (300 ng/kg given as a 10 min infusion) and carboplatin (AUC 4-9) were assessed. 45 of these patients were chemotherapy naive (CN-RMP) and 42 had received one prior course of chemotherapy (CP-RMP). Neurological impairment, performance status and steroid use were measured prior to dosing at each cycle and tumour volume by 3-D MRI at the end of cycles 2, 4, 6, 9 and 12. Clinical evaluation of response demonstrated that 61% of CN-RMP patients were either stable or improved whilst this was 39% for CP-RMP patients, of which 37% and 8% improved respectively. Radiological evaluation showed 79% of CN-RMP patients were either stable, partial or complete responses and 24% for CP-RMP patients, of which 32% and 5% were CR or PR respectively. The median duration of response was 30.3 weeks in CN-RMP patients and 19.6 weeks in the CP-RMP group. Lack of response was associated with substantial baseline tumour volume. Drug toxicity was as previously reported for carboplatin. 11 patients had treatment-associated transient focal seizures. These results indicate that RMP-7 and carboplatin have significant activity in recurrent malignant glioma following radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bradykinin; Brain Neoplasms; Carboplatin; Glioma; Humans; Injections, Intravenous; Magnetic Resonance Imaging; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome

RMP-7, a nine amino acid peptide bradykinin agonist, increases the delivery of hydrophilic compounds across the blood-tumour barrier. In this dose ranging study, 14 patients with progressing malignant glioma (9 glioblastoma multiforme, 4 anaplastic astrocytoma, 1 anaplastic oligodendroglioma; age range 31-68 years, baseline Karnofsky range 60-90%, 5 having had prior chemotherapy) were treated with intravenous RMP-7 and carboplatin to assess the safety, tolerability, and side-effect profile of increasing doses of this combination. Carboplatin dosing was by target area under the curve (AUC) according to the Calvert protocol. Patients were allocated to one of five treatment regimes: cohort A (n = 2) received 50 ng/kg RMP-7 and target AUC 5 mg/ml/min carboplatin; cohort B (n = 3) 100 ng/kg RMP-7 + AUC 5; cohort C (n = 2) 100 ng/kg RMP-7 + AUC 7; cohort D (n = 2) 200 ng/kg RMP-7 + AUC 7; cohort E (n = 5) 300 ng/kg RMP-7 + AUC 7. Treatment was given once every 4 weeks with magnetic resonance imaging scans every 2 months. Patients received 37 cycles in total (median 2, range 1-7). The drug combination, as a cancer treatment, was tolerated in all groups. Effects possibly related to RMP-7 included flushing, nausea, headache and mild increase in heart rate, all transient. 3 patients in cohort E experienced grade 3/4 neutropenia and thrombocytopenia. These toxicities are consistent with known effects of carboplatin at this dose range. In cohort E (n = 5) 1 patient improved and another remained stable for > or = 6 months. In summary, the dose was escalated to the maximum dose of RMP-7 given to volunteers without additional related side-effects. The side-effects of the combination were consistent with giving the two drugs alone and would merit further study for efficacy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bradykinin; Brain Neoplasms; Carboplatin; Cohort Studies; Dose-Response Relationship, Drug; Female; Glioma; Hematologic Diseases; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged

The bradykinin analog, RMP-7, was investigated for its ability to increase selectively the transport of 68Ga ethylenediamine tetraacetic acid (EDTA) into recurrent malignant gliomas in nine patients. For each patient, two position emission tomography (PET) studies (one with and one without RMP-7) were performed. For studies with RMP-7, 10 to 300 ng/kg of the compound was infused into the supraophthalmic carotid artery over 15 minutes. In each PET study, a sequence of PET scans was initiated simultaneously with an intravenous bolus of 68Ga EDTA (5-10 mCi). Arterial samples were taken to provide the input function. All PET scans were coregistered to the magnetic resonance (MR) images of the patient. Regions of interest were defined for tumor and normal tissue regions on MR images and were copied to the coregistered PET dynamic images to provide brain tissue-time activity curves. The constant (Ki) for the transport of gallium-68 from plasma to brain tissue was determined using a simple compartmental model. Intracarotid infusion of RMP-7 significantly increased transport into tumor regions with an average increase of 46 +/- 42% (mean +/- standard deviation, p < 0.05). Permeability in normal tissue regions was not significantly increased. Tumors in three of six patients treated with 300 ng/kg RMP-7 and carboplatin had at least a 50% reduction in tumor volume as measured by MR imaging. Intracarotid infusion of RMP-7 is a novel technique for selective delivery of antitumor compounds into brain tumors.

Topics: Adult; Aged; Antineoplastic Agents; Biological Transport; Bradykinin; Brain Neoplasms; Carboplatin; Drug Therapy, Combination; Edetic Acid; Female; Gallium Radioisotopes; Glioma; Humans; Injections, Intra-Arterial; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Tomography, Emission-Computed

The extent of resection in patients with primary brain tumors may affect the quality of life, time to tumor progression, and survival. Currently, the extent of resection during surgery is guided by the visual appearance and consistency of tumor, frozen sections of the margins, intraoperative ultrasound, and frameless navigational systems and intraoperative imaging modalities. A new method that enhances the visualization of an infiltrating tumor and its margins may further aid in obtaining a more complete resection. A study was thus undertaken to assess the staining of brain tumors using Indocyanine green (ICG), a water-soluble emerald green tricarbocynanine dye concomitantly with RMP-7, a bradykinin analog, that selectively increases vascular permeability in brain tumors.. A syngeneic ethyl-nitrosourea-induced F-344 rat cell line (36B-10) was stereotactically implanted into 25 rats, and allowed to mature for 15-18 days. Intracarotid administration of 0.75 ml of RMP-7 at a standard dose of 0.4 microg/ml over 15 min was then infused. Varying doses of ICG (range, 0-60 mg/kg) were then injected 15 min after the RMP-7 infusion ended. The animals were sacrificed 15 min after the ICG infusion was completed, and the brains examined macroscopically and microscopically for evidence of tumor staining.. This study demonstrated consistent staining of the tumor at only slightly lower ICG doses than previously described, however uptake at the tumor margins was evident at much lower doses. Thus the combination of ICG and RMP-7 administered preoperatively may provide visual enhancement of an infiltrating tumor and its margins to help facilitate a radical tumor removal.

Topics: Animals; Biological Transport; Bradykinin; Brain; Brain Neoplasms; Disease Models, Animal; Glioma; Indocyanine Green; Rats; Rats, Inbred F344

The results of animal studies suggest that superselective intra-arterial infusion allows the permeation of a high concentration of chemotherapeutic agents within intracranial neoplasms. In the present report, we review our clinical experience with the 100 intra-arterial infusions of carboplatin in intracranial neoplasms not responsive to other treatment modalities.. Carboplatin was infused in 100 separate sessions (24 patients) as a mean dose of 286+/-60 mg/m2 (range 34-377 mg/m2). RMP-7, a bradykinin analog, was used as an adjunct in 28 sessions (6 patients). The infusions were performed through superselective microcatheterization of the following arteries: internal carotid (n = 39), middle cerebral (n = 61), posterior cerebral (n = 21) and anterior cerebral (n = 10). The frequency of neurological and non-neurological complications, and survival were recorded. In a subset of 10 patients, tumor volume was measured by serial magnetic resonance images to assess therapeutic response to therapy.. The mean age of the patients was 44.5 years (range 26-67 years); 13 were men. The tumors were classified as glioblastoma multiforme (n = 12), metastatic tumor (n = 1), high-grade astrocytoma (n = 6), and anaplastic mixed glioma (n = 5). Follow-up was available for 23 patients (mean 22 months, range 2-69 months). Survival beyond 1 year after initiation of intra-arterial carboplatin therapy was documented in 12 of the 23 patients. A total of 13 neurological complications including seizures (n = 7), transient neurological deficits (n = 5), and ischemic stroke (n = 1) were observed in 100 procedures. A lower frequency of complications occurred in men and in patients who received adjunctive RMP-7. Volumetric analysis of serial magnetic resonance images demonstrated tumor mass reduction in 3 out of 10 patients. An increase in tumor mass ranging from 23% to 230% was observed in the other 7 patients over a period ranging from 2.3 to 37.7 months since initiation of carboplatin therapy.. Superselective intra-arterial administration of carboplatin appears feasible and was associated with predominantly transient neurological complications. The addition of RMP-7 to carboplatin therapy appears to be at least as safe as the administration of carboplatin alone and requires further investigation as a means of chemotherapeutic dose intensification.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Astrocytoma; Bradykinin; Brain Neoplasms; Carboplatin; Carotid Arteries; Cerebral Arteries; Female; Follow-Up Studies; Glioma; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Retrospective Studies; Time Factors

Little is known about modulation by cytokines of major histocompatibility complex (MHC) antigen expression on intracranial tumors in vivo. The ability of cytokines to up-regulate MHC class-1 (MHC-1) antigen expression was investigated first in vitro using three rat glioma cell lines. Immunohistochemistry showed that incubation with recombinant rat interferon-gamma (rrIFN-gamma) increased MHC-1 antigen expression in RG2, C6, and 9L cell lines. Flow cytometric analysis revealed different baseline levels of MHC-1 antigen expression in each line (RG2 lowest, C6 highest), and that these levels increased in all lines after stimulation with 100 U ml(-1) or more of rrIFN-gamma. The antitumor effect of rrIFN-gamma in vivo was evaluated by assessing survival of rats with implanted intracerebral RG2 gliomas after intracarotid infusion of rrIFN-gamma. A high dose of rrIFN-gamma (2.4 x 10(5) U kg(-1)) significantly increased the survival, compared to control (p < 0.02). Intracarotid pre-treatment with the bradykinin analogue RMP-7 did not further increase survival. Immunohistochemical staining of tumor sections after in vivo rrIFN-gamma, infusion showed no clear increase in MHC-1 antigen expression on tumor cells but increased staining for ED2 antigen within tumor tissue, presumably from perivascular cells with MHC class-2 antigen.

Topics: Animals; Antineoplastic Agents; Bradykinin; Brain Neoplasms; Carotid Arteries; Drug Therapy, Combination; Female; Glioma; Histocompatibility Antigens Class I; Immune System; Injections, Intra-Arterial; Interferon-gamma; Neoplasm Transplantation; Rats; Rats, Inbred F344; Recombinant Proteins; Tumor Cells, Cultured

Cereport (RMP-7) enhances delivery of chemotherapeutics into brain tumors by increasing the permeability of the glioma vasculature (i.e. , the blood-brain tumor barrier; BBTB). Its effect on brain tumors has consistently been more robust than that on normal brain. The present experiments tested the hypothesis that the ability of Cereport to increase the permeability of infiltrating glioma colonies increases as the glioma colonies develop, in situ. In an initial preliminary experiment, the significant and selective effects of Cereport in tumor tissue and brain surrounding tumor were verified using [(14)C]carboplatin as a marker, 8 days after implantation of 50,000 RG2 cells. A second preliminary experiment established that the number of tumor cells initially seeded influences the growth rate of the tumor mass. Tumors seeded with 50,000 cells were larger than those seeded with 25,000 cells 3, 5, and 8 days after implantation. Next, the hypothesis that the extent of tumor growth increases Cereport's effects on the BBTB was tested by measuring the concentration of radiolabeled carboplatin in the tumor when 50,000 cells were implanted 3, 8, or 13 days prior to the experiment. While a reliable, approximately twofold increase in carboplatin concentration was seen in the 8- and 13-day-old tumors, no significant effect of Cereport was observed in the tumors that developed only 3 days, in situ. Finally, another test of the hypothesis was made by comparing Cereport's effects on 8-day-old tumors initially seeded with either 50,000 or 25,000 cells (the latter producing a smaller, more slowly developing, tumor mass). Again, significantly higher carboplatin concentrations were seen with Cereport in the 50,000 cell tumors (greater than two-fold increase), compared to the smaller, more slowly developing, 25,000 cell tumors (<30% increase). The tumor and its vasculature were characterized in additional rats implanted with RG2 cells using CD-31, laminin, and bradykinin B(2) receptor immunocytochemistry. Intense B(2) receptor staining was observed on cells within the parenchyma of normal brain and tumor but not on the vasculature of tumor or brain. An extensive network of CD-31 and laminin staining was seen within and around the tumors in all groups, indicating relatively rapid and robust changes in vascularity in response to the gliomas. However, no consistent difference in vascularity between groups was observed to account for the uptake differences seen with Cereport. Col

Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carbon Radioisotopes; Carboplatin; Cell Count; Drug Delivery Systems; Glioma; Male; Neoplasm Transplantation; Neovascularization, Pathologic; Rats; Rats, Inbred F344

Several experiments studied the effects of i.v. infusions of the bradykinin agonist, Cereport (RMP-7), on permeability of the blood-brain tumor barrier in rat gliomas. First, the ability of Cereport to increase uptake of two poorly blood-brain barrier-penetrating drugs (lypophilic paclitaxel and hydrophilic carboplatin) was directly compared to provide new information regarding the scope of delivery effects achieved with Cereport. Next, the increased uptake of platinum into tumor and brain surrounding tumor was shown to closely parallel that of radiolabeled carboplatin, confirming that delivery of a biologically active moiety is increased with Cereport. This study also demonstrated that the elevated tumor levels of platinum persisted for at least 2 h. The enhanced carboplatin uptake was then examined using a novel, high spatial resolution analysis of autoradiography. This revealed that the effects of Cereport were not uniform throughout the tumor, because it especially modified those areas normally impermeable to carboplatin. Finally, a range of i.v. Cereport doses (3.0 and 9.0 microg/kg) was tested in combination with carboplatin to determine whether increased survival might be achieved and to define the relationship between Cereport dose, plasma levels, uptake of carboplatin, and enhanced survival. Survival was enhanced only by the high dose of Cereport; the high dose also produced robust increases in carboplatin uptake and plasma concentrations of Cereport estimated to achieve the K(i), whereas the low dose did not. These data offer fundamental information regarding the effects of Cereport on delivery of chemotherapeutic agents to brain tumors and provide new insight into receptor-mediated permeability of the blood-brain tumor barrier.

Topics: Animals; Antineoplastic Agents; Bradykinin; Brain Neoplasms; Carboplatin; Glioma; Infusions, Intravenous; Male; Paclitaxel; Platinum; Rats; Rats, Inbred F344

Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model.. For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head.. At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 microg/g with Cereport versus 33.6 +/- 3.9 microg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 +/- 9.9 microg/g with Cereport versus 15.4 +/- 3.5 microg/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0.6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administration of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, and 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport.. These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

Topics: Animals; Blood-Brain Barrier; Boron Compounds; Boron Neutron Capture Therapy; Bradykinin; Brain Neoplasms; Glioma; Phenylalanine; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Survival Rate; Tissue Distribution

Animal and human studies have shown increased delivery of radiolabeled compounds across the blood-brain-tumor barrier using intra-arterial (IA) Cereport (RMP-7; Alkermes Inc., Cambridge, MA) with a radiolabeled tracer. This present study assesses the safety, tolerance, and preliminary efficacy of the IA administration of carboplatin with Cereport.. An open-label dose escalation study of IA Cereport (10-300 ng/kg) with 100 mg of IA carboplatin was conducted in 11 patients with recurrent malignant gliomas and 1 patient treated adjuvantly after radiation therapy. Tumor size and laboratory and clinical statuses were assessed.. Adverse events were mainly neurological in nature and corresponded to the anatomic location of the tumor. Karnofsky performance scale scores did not decline, overall, for those patients who had tumor response. Tumor shrinkage was observed in three of six evaluable patients who received a dose of 300 ng/kg with durable responses of 60, 64, and 106+ weeks.. Previous studies have demonstrated increased permeability in human gliomas using IA Cereport. This study demonstrates durable imaging responses using 100 mg of IA carboplatin in combination with Cereport. The drug combination in this patient population seems to be safe and acceptable, providing a novel means of antitumor dose intensification.

Topics: Adult; Aged; Antineoplastic Agents; Bradykinin; Brain Neoplasms; Carboplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Glioma; Humans; Infusions, Intra-Arterial; Karnofsky Performance Status; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Nervous System Diseases; Treatment Outcome

Using the well-characterized F98 rat glioma model, the purpose of the present study was to determine whether the delivery of boronophenylalanine (BPA) could be enhanced by prior administration of the bradykinin analog Cereport (Alkermes, Inc., Cambridge, MA) (previously known as Receptor-Mediated Permeabilizer-7), which produces a transient, pharmacologically mediated opening of the blood-brain barrier.. Two series of experiments were performed in F98 glioma-bearing rats that had received either intracarotid (i.c.) or intravenous infusions of Cereport (at doses ranging from 1.5 to 7.5 microg/kg of body weight), followed by i.c. (or intravenous) injection of BPA (300 mg/kg of body weight). Animals were killed 0.5, 2.5, or 4 hours later, samples of blood, skin, muscle, and eye were obtained, brains were removed, and tumors were excised for boron determination by direct current plasma-atomic emission spectroscopy.. Averaged over all time points, i.c. infusion of Cereport significantly enhanced tumor boron uptake (P = 0.0001), compared with the excipient (saline) control values. Tumor boron values were equivalent at 0.5 (36.0 microg/g) and 2.5 hours (38.5 microg/g) after i.c. administration of Cereport and BPA and then decreased by 33% (to 25.7 microg/g) at 4 hours. These tumor boron uptake values were significantly different (alpha = 0.05), compared with values measured at the corresponding times after i.c. administration of BPA without Cereport (22.6, 21.8, and 15.3 microg/g, respectively). Although no time-related effects were observed, i.c. administration of Cereport followed by intravenous administration of BPA also significantly enhanced (alpha = 0.05) tumor boron uptake at 0.5, 2.5, and 4 hours (27.4, 30.3, and 28.0 microg/g, respectively), compared with values obtained without Cereport (11.3, 13.4, and 15.2 microg/g, respectively). Boron levels in normal brain tissue from tumor-bearing and non-tumor-bearing cerebral hemispheres and in blood were not significantly different from those measured in saline-treated control animals.. This study established that i.c. infusion of Cereport significantly increased delivery of BPA to F98 rat gliomas, and this could enhance the efficacy of boron neutron capture therapy of this tumor.

Topics: Animals; Boron Compounds; Boron Neutron Capture Therapy; Bradykinin; Brain Neoplasms; Carotid Arteries; Dose-Response Relationship, Drug; Glioma; Injections, Intra-Arterial; Injections, Intravenous; Phenylalanine; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Tissue Distribution

Cereport (RMP-7) is a selective bradykinin B2 receptor agonist which increases the permeability of the 'blood-brain tumour barrier' (BBTB) to increase delivery of chemotherapeutic agents to brain tumours. A series of experiments was performed in an RG2 rodent model of glioma to evaluate and refine intravenous (i.v.) parameters to optimize Cereport's clinical utility. The first experiment demonstrated that while carboplatin levels were increased by twofold when given as a bolus during the Cereport infusion, no increase in carboplatin levels were seen when Cereport and carboplatin were simultaneously co-infused for 15 min. A subsequent experiment established that a major factor responsible for the lack of an effect with the co-infusion paradigm was tachyphylaxis to Cereport during the 15 min infusion, for a progressively diminished response to Cereport occurred over that time frame, as plasma levels of carboplatin were rising. A final experiment adjusted the timing of the Cereport and carboplatin infusions so that higher plasma carboplatin levels were achieved prior to initiating the Cereport infusion. Significant uptake effects were achieved when the carboplatin infusion preceded the Cereport infusion by 10 min (i.e. 5 min overlap in the delivery of the two agents). Collectively, these data provide the first systematic evaluation of dosing parameters involving receptor-mediated changes in BBTB permeability and provide new information regarding the pharmacodynamics and potential clinical use of Cereport.

Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carboplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Glioma; Male; Neoplasm Transplantation; Rats; Rats, Inbred F344; Tachyphylaxis

Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain tumors. The bradykinin B2 receptor agonist, Cereport (RMP-7), selectively increases permeability of the vasculature supplying brain tumors in both animal models and humans. The present study was conducted to characterize the effects of dexamethasone on the blood-brain tumor barrier and its potential interaction with Cereport's ability to enhance penetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice a day) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutive days. After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 micrograms/kg) and a bolus of [14C]carboplatin. The levels of [14C]carboplatin (nCi/g) in the tumor and nontumor regions were determined at 1, 14, or 24 h after the last dose of dexamethasone. Dexamethasone, alone, significantly decreased the levels of radiolabeled carboplatin permeating the tumor (19%), although there were no significant differences between any of the time points examined. Cereport administration significantly increased levels of carboplatin in the tumor, independent of whether or not dexamethasone was given (46% with and 49% without). Although the relative effects of Cereport on tumor carboplatin levels were not affected by dexamethasone, the absolute levels achieved with Cereport were modestly reduced (44 nCi/g versus 55.5 nCi/g of [14C]carboplatin, with and without dexamethasone, respectively). Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery.

Topics: Animals; Blood-Brain Barrier; Body Weight; Bradykinin; Brain Neoplasms; Carboplatin; Depression, Chemical; Dexamethasone; Drug Administration Schedule; Glioma; Male; Neoplasm Transplantation; Organ Size; Permeability; Rats; Rats, Inbred F344; Receptor, Bradykinin B2; Receptors, Bradykinin; Tumor Cells, Cultured

Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.

Topics: 3T3 Cells; Animals; Antiviral Agents; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Cell Division; Drug Synergism; Ganciclovir; Genetic Therapy; Glioma; Infusions, Intravenous; Mice; Neoplasms, Experimental; Rats; Rats, Sprague-Dawley; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured

A blood-tumor barrier (BTB) limits delivery of antitumor agents to brain tumors. This study sought to determine whether dexamethasone (DXN) treatment of rats with intracranial gliomas would 1) further impair delivery of carboplatin to brain tumors, and 2) whether intracarotid infusion of the bradykinin analog, RMP-7, would improve delivery during concurrent DXN treatment. Wistar rats with RG2 gliomas were utilized and a unidirectional transport, Ki, of radiolabeled [14C] carboplatin was determined using quantitative autoradiography. In DXN pretreatment animals, 3 mg/kg/day of DXN was administered intraperitoneally for 3 days prior to Ki determinations. At 10 days after tumor implantation, Ki of [14C] carboplatin into DXN-treated tumors and brain surrounding tumor (BST) was significantly lower compared to non-DXN treated tumors and BST (3.30 +/- 0.91 vs. 4.47 +/- 1.80, p < 0.05, and 0.94 +/- 0.84 vs. 2.18 +/- 0.79, p < 0.05, respectively). Intracarotid infusion of RMP-7 (0.1 mg/kg/min) significantly increased the Ki for carboplatin in DXN-treated tumors (6.35 +/- 3.10 vs. 3.30 +/- 0.91, p < 0.01), however, RMP-7 increased Ki to a greater extent in tumors not pretreated with DXN (12.07 +/- 3.60 vs. 4.47 +/- 1.80, p < 0.0001). Our studies show that dexamethasone decreases transport of carboplatin into brain tumors. Intracarotid infusion of RMP-7 selectively increases carboplatin transport to tumors.

Topics: Animals; Antineoplastic Agents; Autoradiography; Biological Transport; Bradykinin; Brain; Brain Neoplasms; Carbon Radioisotopes; Carboplatin; Dexamethasone; Female; Glioma; Infusions, Intra-Arterial; Kinetics; Rats; Rats, Wistar; Tissue Distribution

The effect of intracarotid infusion of the bradykinin analog, RMP-7, on blood-to-tumor and blood-to-brain transport of three cytokines were investigated. Wistar rats with RG2 gliomas were utilized and a unidirectional transfer constant, Ki, was determined using quantitative autoradiography. Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2) were labeled with 125Iodine for quantitative transport studies using autoradiography. Radiolabeled cytokines were injected as an intravenous bolus. Intracarotid infusion of RMP-7 (0.1 microgram kg-1 min-1) increased the selective transport to tumors of IFN-gamma by 3.97-fold (p < 0.005), of TNF-alpha by 5.30-fold (p < 0.005), and of IL-2 by 4.34-fold (p < 0.005), compared to intracarotid saline infusion. To determine whether the increased IFN-gamma or TNF-alpha transport to tumors with RMP-7 could enhance expression of intercellular adhesion molecule 1 (ICAM-1) in tumors, ICAM-1 expression in RG2 glioma was evaluated by immunohistochemistry. Both IFN-gamma and TNF-alpha increased ICAM-1 expression of RG2 cells in vitro. In vivo, intracarotid infusion of IFN-gamma combined with RMP-7 significantly enhanced ICAM-1 expression in intracerebral RG2 gliomas compared to infusion of IFN-gamma without RMP-7. Expression of ICAM-1 was not enhanced by TNF-alpha combined with RMP-7. Intracarotid infusion of RMP-7 is a novel method of cytokines delivery to brain tumors.

Topics: Animals; Biological Transport; Bradykinin; Brain Neoplasms; Capillary Permeability; Cytokines; Female; Glioma; Infusions, Intra-Arterial; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-2; Iodine Radioisotopes; Neoplasm Transplantation; Rats; Rats, Wistar; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

This study sought to determine whether dexamethasone (DXN) treatment of rats with intracranial gliomas would 1) further impair delivery of carboplatin to brain tumors, and 2) whether intracarotid infusion of the bradykinin analog, RMP-7, would improve delivery during concurrent DXN treatment. In DXN pretreated animals, 3 mg/kg/day of DXN was administered intraperitoneally for 3 days prior to Ki determinations. Ki of [14C] carboplatin into DXN-treated tumors and brain surrounding tumor (BST) was significantly lower compared to non-DXN treated tumors and BST (3.30 +/- 0.91 vs. 4.47 +/- 1.80, p < 0.05, and 0.94 +/- 0.84 vs. 2.18 +/- 0.79, p < 0.05, respectively). Intracarotid infusion of RMP-7 significantly increased the Ki for carboplatin in DXN-treated tumors (6.35 +/- 3.10 vs. 3.30 +/- 0.91, p < 0.01), however, RMP-7 increased Ki to a greater extent in tumors not pretreated with DXN (12.07 +/- 3.60 vs. 4.47 +/- 1.80, p < 0.0001). Dexamethasone decreases transport of carboplatin into brain tumors. Intracarotid infusion of RMP-7 selectively increases carboplatin transport to tumors.

Topics: Animals; Antineoplastic Agents; Bradykinin; Carboplatin; Carotid Arteries; Dexamethasone; Female; Glioma; Glucocorticoids; Infusions, Intra-Arterial; Permeability; Rats; Rats, Wistar

Rats implanted with RG-2 gliomas were administered i.v. RMP-7 and [14C]carboplatin. Changes in the permeability of the blood-brain barrier to carboplatin were determined using quantitative autoradiography. i.v. infusions of RMP-7 induced an increase in the permeability of the vascular barrier within the tumor to carboplatin. Additionally, permeability of brain tissue proximal to, but clearly outside the tumor mass, was also increased. Progressively less uptake of [14C]carboplatin was observed as distance from the tumor border increased. The increases in permeability induced by RMP-7 occurred in a dose-related fashion. No increase in carboplatin level was observed in several nonbrain tissues, including sciatic nerve, retina, heart, lung, liver, kidney, and spleen. Finally, the permeabilizing effects of RMP-7 were shown to occur independent of histaminergic or hypotensive mechanisms. These data provide additional insight into the permeabilizing effects and mechanism of RMP-7 and offer additional support for the therapeutic utility of this novel compound as an adjunctive treatment for human gliomas.

Topics: Animals; Antineoplastic Agents; Autoradiography; Blood-Brain Barrier; Bradykinin; Brain; Brain Neoplasms; Capillary Permeability; Carbon Radioisotopes; Carboplatin; Dose-Response Relationship, Drug; Drug Interactions; Female; Glioma; Histamine; Hypotension; Rats; Rats, Wistar

Intracarotid infusion of the bradykinin analog, RMP-7, can increase permeability in brain tumor capillaries. This study sought to determine the following: 1) the unidirectional transport, Ki, of radiolabeled [14C]carboplatin into brain tumors with either intravenous or intracarotid RMP-7 infusions; 2) the duration and extent of increased permeability in tumor capillaries during continuous RMP-7 infusions; and 3) the effect on survival of carboplatin combined with RMP-7 treatment in rats with gliomas.. Wistar rats with RG2 gliomas were used, and a unidirectional transfer constant, Ki, was determined using quantitative autoradiography. In the survival study, the rats were treated with intra-arterial carboplatin and RMP-7 at Days 5 and 7 after tumor implantation.. Intracarotid infusion of RMP-7 for 15 minutes increased the transport of [14C]carboplatin to tumors by 2.7-fold, as compared with saline infusion alone (P < 0.001). The transports of [14C]dextran and [14C]carboplatin into tumors were significantly higher with 15 minutes of intracarotid infusion of RMP-7 (0.1 microgram/kg/min), compared to those with 10-, 30-, or 60-minute infusions (P < 0.01). Rats treated at Days 5 and 7 after tumor implantation with carboplatin alone (10 mg/kg) exhibited a modest increase in survival at 31 days (37%, compared to < 10% of controls), while those given the combination of carboplatin with RMP-7 exhibited a significantly higher survival rate (74%).. Intracarotid infusion of RMP-7 can selectively increase transport of carboplatin into brain tumors and results in higher survival in rats with gliomas. These findings support the use of intracarotid infusion of RMP-7 to enhance the delivery of carboplatin to patients with malignant brain tumors.

Topics: Animals; Antineoplastic Agents; Autoradiography; Blood-Brain Barrier; Bradykinin; Brain; Brain Neoplasms; Capillary Permeability; Carboplatin; Carotid Arteries; Dose-Response Relationship, Drug; Female; Glioma; Infusions, Intra-Arterial; Infusions, Intravenous; Rats; Rats, Wistar; Survival Rate

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.

Topics: Animals; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carboplatin; Dose-Response Relationship, Drug; Female; Glioma; Kinetics; Rats; Rats, Wistar; Tumor Cells, Cultured

The bradykinin analog, RMP-7, was investigated for its ability to selectively increase uptake of molecular tracers in RG2 glial tumors. When infused in low doses (0.1 microgram/kg/min) through the intracarotid artery ipsilateral to RG2 gliomas in rats, RMP-7 significantly increased the permeability of tumor capillaries to methotrexate and to four other tracers of varying molecular weights, compared to intracarotid infusion of vehicle alone. Tracers used to examine permeability included radiolabeled alpha-aminoisobutyric acid (M(r) 103 D), sucrose (M(r) 342 D), methotrexate (M(r) 454.5 D), inulin (M(r) 5000 D), and dextran (M(r) 70,000 D). Permeability was expressed as the unidirectional transfer constant, Ki (microliters/gm/min). The permeability (Ki) of tumors in the RMP-7 group compared to the vehicle control group was as follows: alpha-aminoisobutyric acid, 35.3 +/- 9.11 versus 12.7 +/- 4.56 (p < 0.001); sucrose, 16.5 +/- 3.83 versus 9.28 +/- 3.12 (p < 0.05); methotrexate, 26.3 +/- 10.3 versus 8.98 +/- 6.78 (p < 0.005); inulin, 13.5 +/- 3.23 versus 6.55 +/- 4.32 (p < 0.005); dextran, 15.2 +/- 3.42 versus 1.47 +/- 1.24 (p < 0.001). The permeability of RG2 gliomas to high-molecular-weight dextran (70,000 D) was 10.3-fold higher in the RMP-7 group than in the vehicle control group. Intracarotid infusion of RMP-7 did not significantly increase the blood volume in tumor or brain tissue. The permeability of normal brain capillaries was unaffected by intracarotid infusion of 0.1 microgram/kg/min RMP-7 relative to that achieved in tumor. These data support the idea that intracarotid infusion of RMP-7 will be a useful technique for selective delivery of antitumor compounds to brain tumors.

Topics: Animals; Autoradiography; Blood Pressure; Blood Volume; Blood-Brain Barrier; Bradykinin; Brain; Brain Neoplasms; Capillaries; Capillary Permeability; Carotid Arteries; Female; Glioma; Infusions, Intra-Arterial; Rats; Rats, Wistar