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

The effects of intravenous (IV) infusion of human recombinant tumor necrosis factor-alpha (rTNF-alpha, Cetus) on normal brain and malignant glioma in rats were examined. Twelve Fischer 344 rats were given either a single injection of 10(6) U rTNF-alpha or injections of 5 x 10(5) U rTNF-alpha for three days. One day post-rTNF-alpha injection(s), rats were injected IV with horseradish peroxidase (HRP) to determine blood-brain barrier (BBB) breakdown and, one hour later, were perfused with an aldehyde fixative and processed for histologic examination. Treatment of normal rats with rTNF-alpha by either dosage or schedule caused no remarkable histopathologic changes in the brain and no alteration in BBB integrity. Human glioma models were produced by intracerebal inoculation of 10(4) syngeneic RT-2 glioma cells into the right parietal lobe of 30 rats. Animals received single IV injections of 10(6) U human rTNF-alpha or its excipient (TNF-E) as above on day 3, 7, or 10 post-tumor inoculation or multiple injections of 5 x 10(5) U rTNF-alpha beginning on day 7, 10, or 12 post-tumor inoculation. With a single IV injection of either rTNF-alpha or its excipient, 3-day models showed a similar pattern of HRP extravasation limited to the extracellular space of the tumor inoculation site. In 7-day models treated with a single IV injection of rTNF-alpha or TNF-E, HRP extravasated throughout the tumor, but did not exceed peritumoral margins. In 10-day models treated with a single injection of TNF-E, HRP was found only in the tumor and immediate peritumoral regions while rTNF-alpha-treated rats showed more extensive areas of BBB breakdown with HRP evident throughout the entire right hemisphere and extending via the corpus callosum into the contralateral hemisphere. Pericapillary halos were also evident around the small blood vessels within the edematous areas of the corpus callosum. Within tumors, hemorrhagic necrosis and adherence of neutrophils to vessels was observed only in animals treated with rTNF-alpha at 10 days post-tumor inoculation. Multiple IV injections of rTNF-alpha in 7 and 10-day models triggered widespread hemorrhagic necrosis, neutrophil adherence and infiltration in the tumor. There was also extravasation and diffusion of HRP from the site of glioma into the contralateral hemisphere. Twelve-day models treated with multiple rTNF-alpha injections, in addition, showed irregular luminal surfaces and gaps between adjacent endothelial cells of tumor vasculature.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acute effects of human recombinant tumor necrosis factor-alpha on the cerebral vasculature of the rat in both normal brain and in an experimental glioma model. 171 71

Morphological changes of the basement membrane associated with endothelial proliferation in astrocytic tumors are studied in this report. Laminin is known to be a specific glycoprotein of basement membranes. We applied this characteristic of laminin to enable us to observe various characteristics of the basement membrane. The presence of laminin in 13 glioblastomas, 15 anaplastic astrocytomas, 7 astrocytomas, and 6 pilocytic astrocytomas was examined by peroxidase-antiperoxidase (PAP) staining of formalin-fixed and paraffin-embedded surgical specimens. White matter from five normal cerebral hemispheres obtained during autopsy and subsequently embedded using the same method, were used as a control. Laminin was observed at the glioma-mesenchymal junction in astrocytic tumors, and the deposits of laminin made the tumor vasculature come into intense relief. The destructive changes of the basement membrane, including disruption, thickening, disconnection, dissociation, winding, and conjunction, became greater with progressive endothelial proliferation in astrocytic tumors. Those changes were seen to be most remarkable in glioblastoma. In addition, there was a marked variety of morphological change in the basement membrane in different areas of glioblastomas, although the changes were almost constant in other astrocytic tumors. We present a schematic hypothesis of the stages of angiogenesis in glioblastoma based on the above morphological changes of the basement membrane and discuss it in this report.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Morphological changes in basement membrane associated with endothelial proliferation in astrocytic tumors--an immunohistochemical study of laminin]. 247 10

The distribution of type VI collagen was examined immunohistochemically in normal tissues and in 24 human gliomas and six medulloblastomas. Its localization in the neoplasms was compared with that of fibronectin and glioma-mesenchymal extracellular matrix (GMEM) glycoprotein. In normal non-neural tissues type VI collagen was demonstrated in the interstitial connective tissue and in some basement membranes. In normal brain it was localized to the vasculature, leptomeninges, and pial-glial membrane. In neoplasms type VI collagen and fibronectin codistributed in the vasculature and stromal connective tissue. The GMEM glycoprotein, as identified by monoclonal antibody (MAb) 81C6, and a related glioma-mesenchymal matrix antigen identified by MAb 2A6, were expressed not only in the tumor vasculature and connective tissue, but also within the tumor parenchyma in association with glioma cells. The staining intensity was variable in 20 malignant gliomas and weak to absent in two pilocytic astrocytomas and six medulloblastomas. An oligodendroglioma and ependymoma both expressed the 2A6 epitope, but staining with MAb 81C6 was weak to absent. The antigens identified by MAb 81C6 and MAb 2A6 represent the only recognized extracellular matrix components, other than proteoglycans, that are associated with glioma cells in vivo. As prominent constituents of the pericellular matrix, they may be involved in recognized matrix functions such as the modulation of cell adhesion and migration.
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PMID:Distribution of type VI collagen in human gliomas: comparison with fibronectin and glioma-mesenchymal matrix glycoprotein. 365 35

The extracellular matrix is involved in many aspects of tumor cell biology, including tumor invasion and metastasis. 2A6 and 81C6 are murine monoclonal antibodies that identify glioma-mesenchymal extracellular matrix antigens. The 81C6 antigen is a high molecular weight glycoprotein composed of Mr 230,000 subunits. The expression of 2A6 antigen, 81C6 glycoprotein, fibronectin (FN), and laminin (LN) was examined immunohistochemically in ten malignant gliomas (MG) and four medulloblastomas (MBT). 2A6 and 81C6 were expressed in similar patterns by the neoplastic neuroepithelial cells in 9/10 MG and 1/4 MBT. The staining was typically diffuse and amorphous, without visualization of distinct cell bodies or processes. Less frequently, antigen was detected within tumor cell cytoplasm. In most tumors the staining was greatest in the perivascular regions. In two MG, 2A6 and 81C6 were expressed only by a subpopulation of neoplastic cells. Although intense staining was also associated with hyperplastic vascular and mesenchymal cells, many small and medium size blood vessels stained weakly or not at all. In contrast, FN and LN were expressed uniformly and intensely in the tumor vasculature, but were not expressed by neoplastic neuroepithelial cells. The 2A6 antigen and 81C6 glycoprotein are immunohistochemically distinct from FN and LN. These monoclonal antibody-defined antigens are heterogeneously expressed by neoplastic neuroepithelial cells and hyperplastic vascular-mesenchymal elements in MG and MBT. The 2A6 and 81C6 monoclonal antibodies will be useful reagents in the investigation of the extracellular matrix of malignant neuroepithelial neoplasms.
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PMID:Immunolocalization of monoclonal antibody-defined extracellular matrix antigens in human brain tumors. 403 75

Two weeks after the inoculation of 1.5 x 10(5) 9L glioma cells into the rat brain, the uptake of radiolabelled drugs into the brain and the experimental 9L glioma during the first cerebral circulation was measured with a liquid scintillation counter and analyzed by the method of Oldendorf (1970). The expression of P-glycoprotein, which is known to be associated with the efflux of drugs, was also studied, using anti-P-glycoprotein monoclonal antibody, C-219. Furthermore, the ultrastructure of brain capillaries, tumor vessels, and glioma cells was studied by conventional and immunoelectron microscopy. Sucrose (control), the transport of which through the blood-brain barrier is known to be negligible, accumulated to fivefold higher levels in the tumor than in normal brain. Ranimustine (MCNU), 5-fluorouracil (5-FU), and doxorubicin showed little accumulation in the normal brain, whereas nimustine (ACNU) showed an increased accumulation. MCNU and doxorubicin showed negligible accumulation in the glioma cells despite diffusion into the tumor interstitial space. In contrast, ACNU and 5-FU showed an increased accumulation in tumor cells. The accumulation of 5-FU in the cultured 9L glioma cells was decreased by ATP inhibitors or by low temperature. Although both brain capillary endothelial cells and glioma cell membrane were immunohistochemically positive for P-glycoprotein, the tumor vasculature showed low expression of P-glycoprotein. The endothelial cells of tumor vessels ultrastructurally showed increased fenestrations, swelling, and disrupted junctions. Accordingly, it is suggested that hydrophobic drugs such as doxorubicin, being pumped out by P-glycoprotein, do not accumulate in 9L glioma cells as do other lipophilic drugs such as ACNU, or drugs such as 5-FU, which accumulate by a carrier-mediated mechanism.
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PMID:Uptake of drugs and expression of P-glycoprotein in the rat 9L glioma. 810 17

The angiogenic phenotype is associated with hyperpermeable capillaries. Through treatment with angiogenesis inhibitors capillary permeability may be reduced, and it can be anticipated that cytotoxic agents coadministered may be adversely affected. The current investigation examined this possibility for the combination of TNP-470, an angiogenesis inhibitor, and temozolomide (TMZ), a DNA-alkylating agent with demonstrated activity in brain tumors. TNP-470 (30 mg/kg) was given s.c. on days 6, 8, 10, 12, and 14 following s.c. implantation of rat C6 glioma cells in Sprague-Dawley rats. On the 15th day following tumor implantation, control (no TNP-470) and treated rats received 40 mg/kg of TMZ intraarterially. Prior to dosing, a linear microdialysis probe was placed in the tumor to collect interstitial fluid. Plasma and interstitial fluid samples were collected for 8 h and measured for TMZ by a high-performance liquid chromatography assay. Pharmacokinetic parameters for TMZ were calculated by noncompartmental methods. Total systemic clearance (39.8 +/- 7 versus 44.2 +/- 14 ml min(-1) kg(-1)) and volume of distribution (5.4 +/- 2 versus 5.2 +/- 0.8 L kg(-1)) were not significantly different in control and TNP-470-treated animals. However, the mean TMZ area under the interstitial fluid concentration-time curve was reduced by 25% in the TNP-470-treated group compared to the control (5450 +/- 1892 versus 4120 +/- 1790 micrograms min ml(-1); P < 0.05). It appears that TNP-470 caused this reduction in the tumor uptake of TMZ by its pharmacodynamic action on the tumor vasculature. Since combination regimens using angiogenesis inhibitors and cytotoxic drugs will be needed to determine how such combinations can be used effectively. The current animal model, which utilized tumor microdialysis, can serve as a model to further analyze combination chemotherapy.
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PMID:Uptake of temozolomide in a rat glioma model in the presence and absence of the angiogenesis inhibitor TNP-470. 861 36

We have recently shown that VEGF functions as a survival factor for newly formed vessels during developmental neovascularization, but is not required for maintenance of mature vessels. Reasoning that expanding tumors contain a significant fraction of newly formed and remodeling vessels, we examined whether abrupt withdrawal of VEGF will result in regression of preformed tumor vessels. Using a tetracycline-regulated VEGF expression system in xenografted C6 glioma cells, we showed that shutting off VEGF production leads to detachment of endothelial cells from the walls of preformed vessels and their subsequent death by apoptosis. Vascular collapse then leads to hemorrhages and extensive tumor necrosis. These results suggest that enforced withdrawal of vascular survival factors can be applied to target preformed tumor vasculature in established tumors. The system was also used to examine phenotypes resulting from over-expression of VEGF. When expression of the transfected VEGF cDNA was continuously "on," tumors became hyper-vascularized with abnormally large vessels, presumably arising from excessive fusions. Tumors were significantly less necrotic, suggesting that necrosis in these tumors is the result of insufficient angiogenesis.
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PMID:Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. 923 51

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.
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PMID:Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. 991 26

The degree of tumor malignancy generally correlates to tumor grade, and the direct measurement of tumor vasculature is desired. Dynamic susceptibility contrast magnetic resonance imaging can provide relative cerebral blood volume and, therefore, is one of the most reliable methods to evaluate tumor vasculature in vivo. Tumor vessel size is extremely variable due to complex tumor angiogenesis, and the gradient-echo echo-planar imaging (GE-EPI) technique, which is sensitive to the total vascular bed, is well suited for this purpose. As many studies have shown, dynamic susceptibility contrast magnetic resonance imaging is more useful for grading glioma than conventional magnetic resonance imaging. We found that this technique can also provide supplementary information to differentiate between malignant lymphoma and glioma because the absence of tumor neovascularization of malignant lymphoma leads to low rCBV, which is in contrast to those of malignant gliomas. Indeed, this technique can be used for the differentiation of extra-axial tumors such as between meningioma and neurinoma. Recently, this technique has been focused toward determining the stereotactic biopsy site, monitoring the embolization of effect in meningioma, or evaluation of treatment effects after radiation therapy. However, the value of tumor rCBV is affected by many conditions such as the T1 relaxivity effects of gadolinium in the extravascular space. To establish the usefulness of this technique, further examination will be needed.
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PMID:Value of dynamic susceptibility contrast magnetic resonance imaging in the evaluation of intracranial tumors. 1055 26

Angiotensin peptides are potent vasoconstrictors, cell growth factors, and neuromodulators in normal and pathological situations. To assess the potential role of the angiotensins in brain tumor-associated vessels, the expression of the enzymes of the angiotensin cascade were evaluated in these tumors. The production of these bioactive peptides is dependent on the activities of exopeptidases, including several aminopeptidases and carboxypeptidases, producing angiotensin (Ang) I, II, III, IV and Ang 1-7. Human cerebral parenchymal and glioblastoma cells expressed renin, and tumor vasculature, but not glioblastoma cells, expressed angiotensin-converting enzyme. High aminopeptidase A (APA) activity, but no aminopeptidase N/B activity, was observed in human brain tumor vasculature, suggesting a predominant production of Ang III. Grafting of rat glioma cells in rat brains yielded tumors with high APA and low aminopeptidase N/B activities in tumor vessels, confirming human results. Tumor growth and APA activity in tumor vessels were not affected by chronic angiotensin-converting enzyme inhibition. The brain-derived EC219 endothelial cells expressed high APA activity, which was not involved in endothelial cell proliferation, but was down-regulated by exposure of cells to transforming growth factor-beta (TGF beta) or to TGF beta-secreting tumor cells, suggesting a role for this peptide in the control of APA activity in cerebral vasculature. Thus, APA is a potential marker of chronic dysfunction, involving loss of TGF beta function, of the metabolic blood-brain barrier, but not of neovascularization.
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PMID:Regulation of aminopeptidase A in human brain tumor vasculature: evidence for a role of transforming growth factor-beta. 1087 47


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