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Cancer Nov 2005Ninety 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...
BACKGROUND
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.
METHODS
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).
RESULTS
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.
CONCLUSIONS
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
PubMed: 16177987
DOI: 10.1002/cncr.21403 -
Cancer Sep 2005Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to... (Clinical Trial)
Clinical Trial
BACKGROUND
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.
METHODS
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).
RESULTS
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.
CONCLUSIONS
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
PubMed: 16078267
DOI: 10.1002/cncr.21301 -
Molecular Medicine (Cambridge, Mass.) Aug 1997HIV-1 invades the central nervous system early after infection when macrophage infiltration of the brain is low but myelin pallor is suggestive of blood-brain-barrier...
BACKGROUND
HIV-1 invades the central nervous system early after infection when macrophage infiltration of the brain is low but myelin pallor is suggestive of blood-brain-barrier damage. High-level plasma viremia is a likely source of brain infection. To understand the invasion route, we investigated virus penetration across in vitro models with contrasting paracellular permeability subjected to TNF-alpha.
MATERIALS AND METHODS
Blood-brain-barrier models constructed with human brain microvascular endothelial cells, fetal astrocytes, and collagen I or fibronectin matrix responded in a dose-related fashion to cytokines and ligands modulating paracellular permeability and cell migration. Virus penetration was measured by infectious and quantitative HIV-1 RNA assays. Barrier permeability was determined using inulin or dextran.
RESULTS
Cell-free HIV-1 was retained by the blood-brain barrier with close to 100% efficiency. TNF-alpha increased virus penetration by a paracellular route in a dose-dependent manner proportionately to basal permeability. Brain endothelial cells were the main barrier to HIV-1. HIV-1 with monocytes attracted monocyte migration into the brain chamber.
CONCLUSIONS
Early after the infection, the blood-brain barrier protects the brain from HIV-1. Immune mediators, such as TNF-alpha, open a paracellular route for the virus into the brain. The virus and viral proteins stimulate brain microglia and macrophages to attract monocytes into the brain. Infiltrating macrophages cause progression of HIV-1 encephalitis.
Topics: Astrocytes; Blood-Brain Barrier; Bradykinin; Cell Culture Techniques; Cell Membrane Permeability; Cell Movement; Cells, Cultured; Child; Collagen; Electric Impedance; Endothelium, Vascular; Extracellular Matrix; Fibronectins; HIV Core Protein p24; HIV-1; Humans; Interleukin-6; Monocytes; RNA, Viral; Tumor Necrosis Factor-alpha
PubMed: 9307983
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Aug 2001The outcome of herpes simplex virus (HSV) infections manifesting as encephalitis in healthy or immunocompromised individuals is generally very poor with mortality rates...
The outcome of herpes simplex virus (HSV) infections manifesting as encephalitis in healthy or immunocompromised individuals is generally very poor with mortality rates of about 8 to 28% with treatment. The long-term prognosis of survivors is often problematic, posing the need for alternative treatments that may decrease the mortality and morbidity associated with herpes encephalitis. This study addresses one such approach that includes a temporary permeabilization of the blood-brain barrier during treatment with acyclovir (ACV). In these studies we utilized a synthetic bradykinin analog, Cereport (RMP-7), in conjunction with ACV to treat HSV infection of the brain in a rat model. Cereport, infused intravenously via the jugular vein, was shown to increase [(14)C]ACV uptake in both the HSV-1-infected and -uninfected rat brain by approximately two- to threefold, correlating with enhanced efficacy of ACV in various brain compartments. In another series of experiments to determine efficacy, various doses of unlabeled ACV were administered during infusion with RMP-7. The decrease in viral titers in the temporal regions of the brain after 5 days of treatment suggested that this approach enhanced the efficacy of ACV treatment. These data indicated that Cereport infused with ACV enhances both the penetration and efficacy of this drug in the treatment of an experimental HSV-1 infection of the rat brain.
Topics: Acyclovir; Animals; Antiviral Agents; Biological Availability; Blood-Brain Barrier; Bradykinin; Brain; Capillary Permeability; Encephalitis, Herpes Simplex; Herpesvirus 1, Human; Infusions, Intravenous; Male; Rats; Rats, Inbred F344; Tissue Distribution
PubMed: 11451691
DOI: 10.1128/AAC.45.8.2316-2323.2001 -
Cereport (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone.Neuro-oncology Oct 1999Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain...
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
PubMed: 11550318
DOI: 10.1093/neuonc/1.4.268 -
British Journal of Cancer Jun 1999Cereport (RMP-7) is a selective bradykinin B2 receptor agonist which increases the permeability of the 'blood-brain tumour barrier' (BBTB) to increase delivery of...
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
PubMed: 10362103
DOI: 10.1038/sj.bjc.6690450