Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Modified immunoregulation associated with interferon-gamma treatment of rat glioma. 1142 16

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.
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PMID:Cereport (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone. 1155 Mar 18

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.
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PMID:A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. 1267 81

Development of any therapeutic modality can be facilitated by the use of the appropriate animal models to assess its efficacy. This report primarily will focus on our studies using the F98 and 9L rat glioma models to evaluate the effectiveness of boron neutron capture therapy (BNCT) of brain tumors. Following intracerebral implantation the biological behavior of each tumor resembles that of human high grade gliomas in a number of ways. In both models, glioma cells were implanted intracerebrally into syngeneic Fischer rats and approximately 10-14 days later BNCT was initiated at the Brookhaven National Laboratory Medical Research Reactor. Two low molecular weight (M(r) < 210Da) 10B-containing drugs, boronophenylalanine (BPA) and/or sodium borocaptate (BSH) were used as capture agents, either alone or in combination with each other. The 9L gliosarcoma, which has been difficult to cure by means of either chemo- or radiotherapy alone, was readily curable by BNCT. The best survival data were obtained using BPA at a dose of 1200 mg/kg (64.8mg 10B), administered intraperitoneally (i.p.), with a 100% survival rate at 8 months. In contrast, the F98 glioma has been refractory to all therapeutic modalities. Tumor bearing animals, which had received 500 mg/kg (27 mg 10B) of BPA, or an equivalent amount of BSH i.v., had mean survival time (MST) of 37 and 33 days, respectively, compared to 29 days for irradiated controls. The best survival data with the F98 glioma model were obtained using BPA + BSH in combination, administered intra-arterially via the internal carotid artery (i.c.) with hyperosmotic mannitol induced blood-brain barrier disruption (BBB-D). The MST was 140 days with a cure rate of 25%, compared to a MST of 73 days with a 5% cure rate without BBB-D, and 41 days following i.v. administration of both drugs. A modest but significant increase in MST also was observed in rats that received intracarotid (i.c.) BPA in combination with Cereport (RMP-7), which produced a pharmacologically mediated opening of the BBB. Studies also have been carried out with the F98 glioma to determine whether an X-ray boost could enhance the efficacy of BNCT, and it was shown that there was a significant therapeutic gain. Finally, molecular targeting of the epidermal growth factor receptor (EGFR) has been investigated using F98 glioma cells, which had been transfected with the gene encoding EGFR and, intratumoral injection of boronated EGF as the delivery agent, followed by BNCT. These studies demonstrated that there was specific targeting of EGFR and provided proof of principle for the use of high molecular weight, receptor targeting-boron delivery agents. Finally, a xenograft model for melanoma metastatic to the brain has been developed using a human melanoma (MRA27), stereotactically implanted into the brains of nude rats, and these studies demonstrated that BNCT either cured or significantly prolonged the survival of tumor-bearing rats. It remains to be determined, which, if any, of these experimental approaches will be translated into clinical studies. Be that as it may, rat brain tumor models already have made a significant contribution to the design of clinical BNCT protocols, and should continue to do so in the future.
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PMID:Rat brain tumor models to assess the efficacy of boron neutron capture therapy: a critical evaluation. 1274 3

One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B(2) bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.
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PMID:Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport. 1275 91

Primary central nervous system neoplasms are the second malignancy in children following leukemia. Despite developments in neurosurgery and new drugs in chemotherapy, irradiation is an essential part of the management in most of pediatric brain tumors. A good treatment strategy should consider not only survival but also the quality of life. The new approach of radiotherapy and importance of new drugs in combined treatment are recently considered. This article summarizes the recent clinical trials conducted in pediatric brain tumors management. Results of randomized study of pre-irradiation chemotherapy versus radiotherapy alone for medulloblastoma were presented by SIOP/UKCCSG PNET-3. The French M-SFOP 98 protocol considered hyper-fractionated radiotherapy with reduced boost volume, without chemotherapy and estimated impact on early relapses and intellectual function. The influence of radiotherapy quality on survival in high-risk medulloblastoma patients was evaluated in POG Trial 9031. In the treatment of low-grade glioma in children the effectiveness of novel combination chemotherapy was considered. Role of new drugs as temozolamid, topotecan and RMP-7 was investigated in pediatric high grade glioma and brain stem tumors. Impact of combined treatment on outcome of intracranial germ-cell tumors was investigated as well.
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PMID:A literature review of the recent radiotherapy clinical trials in pediatric brain tumors. 1914 62


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