Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The need for a large animal tumor model in experimental neuro-oncology led us to re-evaluate and to modify the transplantable canine glioma of Wodinsky and Walker. Successive passages of the original tumor brei were made in purebred beagles, from beagle to mongrel, and between various mongrel strains until an intracerebral injection of 0.1 cc on Days 1 to 3 of life produced a 93% incidence of tumor take in all breeds. The mean survival was 13.5 +/- 1.9 days after injection (range, 10 to 19 days) in 10 litters. The tumor was invariably fatal and possessed many of the histological characteristics of human glioblastoma (i.e., capillary proliferation, pseudopallisading, frequent mitotic figures, and multinucleated giant cells). The animals were large enough to be scanned on the Pfizer 450 scanner, and the tumors were visualized in vivo as typical "ring" lesions after the injection of contrast agent. Intravital staining with Evans blue outlined the areas of contrast enhancement observed in the same tumors by computed tomography. The apparent defect in the blood-brain barrier could be explained in part by the absence of endothelial tight junctions on electron microscopy. Stability in the histology and activity of the tumor could be demonstrated after more than 14 months of storage at -70 degrees C. The transplantable canine glioma model has many advantages including low cost, reproducible morphology, a short survival time, and relative safety for the investigator. The large size of the animal preparation allows the use of complex surgical instrumentation and radiographic study, as well as repeated sampling of cerebrospinal and other fluids.
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PMID:Transplantable canine glioma model for use in experimental neuro-oncology. 629 Sep 29

Glioblastomas are high-grade, malignant CNS neoplasms that are nearly always fatal within 12 months of diagnosis. Immunotherapy using proinflammatory cytokines such as IL-2 or IL-12 may prolong survival with glioblastoma. Thymosin-alpha1 (Talpha1) is a thymic hormone and immunemodulator that increase IL-2 production and T-cell proliferation. We examined potential therapeutic effects of Talpha1 in experimental in vivo glioblastoma, and characterized Talpha1's anti-tumor effects in vitro. Rar 9L cells (10(4)) were implanted into the right frontal lobe of adult Long Evans rats that were subsequently treated with vehicle, BCNU, Talpha1, or Talpha1+BCNU from postoperative day 6. Talpha1+BCNU significantly lowered tumor burdens, and increased cure rates. In vitro experiments demonstrated that Talpha1 had no direct effect on viability or mitochondrial function, and instead, it increased expression of pro-apoptosis genes, including FasL, FasR and TNFalpha-R1 (65.89%, 44.08%, and 22.18%, resp.), and increased 9L cell sensitivity to oxidative stress. Moreover, Talpha1 enhanced 9L cell sensitivity to both Granzyme B- and BCNU-mediated killing. The findings suggest that Talpha1 enhances BCNUmediated eradication of glioblastoma in vivo, and that Talpha1 mediates its effects by activating pro-apoptosis mechanisms, rendering neoplastic cells more sensitive to oxidative stress and immune-mediated killing by Granzyme B and chemotherapeutic agents.
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PMID:Potential Role of Thymosin-alpha1 Adjuvant Therapy for Glioblastoma. 2011 37

Blood brain barrier (BBB) disruption is used (pre)clinically as a measure for brain tumor malignancy and grading. During treatment it is one of the parameters followed rigorously to assess therapeutic efficacy. In animal models, both invasive and non-invasive methods are used to determine BBB disruption, among them Evans blue injection prior to sacrifice and T1-weighted magnetic resonance imaging (MRI) post contrast injection. In this study, we have assessed the BBB integrity with the methods mentioned above in two experimental high grade glioma models, namely the GL261 mouse glioblastoma model and the Hs683 human oligodendroglioma model. The GL261 model showed clear BBB integrity loss with both, contrast-enhanced (CE) MRI and Evans blue staining. In contrast, the Hs683 model only displayed BBB disruption with CE-MRI, which was not evident on Evans blue staining, indicating a limited BBB disruption. These results clearly indicate the importance of assessing the BBB integrity status using appropriate methods. Especially when using large therapeutic molecules that have difficulties crossing the BBB, care should be taken with the appropriate BBB disruption assessment studies.
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PMID:In vivo and ex vivo assessment of the blood brain barrier integrity in different glioblastoma animal models. 2499 Aug 26

Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and ¹⁸F-FET uptake in a human xenograft model. Methods: Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. ¹⁸F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; n = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; n = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment (n = 8). Time-activity curves, slope, and tumor-to-brain ratios of ¹⁸F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Results: Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration (P = 0.055) and long-term therapy resulted in a significant decrease (P = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of ¹⁸F-FET uptake were observed in PET and autoradiography (P > 0.05). Conclusion:⁸F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.
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PMID:Influence of Bevacizumab on Blood-Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas. 2815 56

Vascular endothelial growth factor A (VEGF-A) is considered one of the most important factors in tumor angiogenesis, and consequently, a number of therapeutics have been developed to inhibit VEGF signaling. Therapeutic strategies to target brain malignancies, both primary brain tumors, particularly in pediatric patients, and metastases, are lacking, but targeting angiogenesis may be a promising approach. Multiparametric MRI was used to investigate the response of orthotopic SF188^luc pediatric glioblastoma xenografts to small molecule pan-VEGFR inhibitor cediranib and the effects of both cediranib and cross-reactive human/mouse anti-VEGF-A antibody B20-4.1.1 in intracranial MDA-MB-231 LM2-4 breast cancer xenografts over 48 hours. All therapeutic regimens resulted in significant tumor growth delay. In cediranib-treated SF188^luc tumors, this was associated with lower K^trans (compound biomarker of perfusion and vascular permeability) than in vehicle-treated controls. Cediranib also induced significant reductions in both K^trans and apparent diffusion coefficient (ADC) in MDA-MB-231 LM2-4 tumors associated with decreased histologically assessed perfusion. B20-4.1.1 treatment resulted in decreased K^trans, but in the absence of a change in perfusion; a non-significant reduction in vascular permeability, assessed by Evans blue extravasation, was observed in treated tumors. The imaging responses of intracranial MDA-MB-231 LM2-4 tumors to VEGF/VEGFR pathway inhibitors with differing mechanisms of action are subtly different. We show that VEGF pathway blockade resulted in tumor growth retardation and inhibition of tumor vasculature in preclinical models of pediatric glioblastoma and breast cancer brain metastases, suggesting that multiparametric MRI can provide a powerful adjunct to accelerate the development of antiangiogenic therapies for use in these patient populations.
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PMID:Evaluation of the Response of Intracranial Xenografts to VEGF Signaling Inhibition Using Multiparametric MRI. 2878 Mar 87

Glioblastoma (GBM), a highly aggressive form of brain tumor, is a disease marked by extensive invasion into the surrounding brain. Interstitial fluid flow (IFF), or the movement of fluid within the spaces between cells, has been linked to increased invasion of GBM cells. Better characterization of IFF could elucidate underlying mechanisms driving this invasion in vivo. Here, we develop a technique to noninvasively measure interstitial flow velocities in the glioma microenvironment of mice using dynamic contrast-enhanced magnetic resonance imaging (MRI), a common clinical technique. Using our in vitro model as a phantom "tumor" system and in silico models of velocity vector fields, we show we can measure average velocities and accurately reconstruct velocity directions. With our combined MR and analysis method, we show that velocity magnitudes are similar across four human GBM cell line xenograft models and the direction of fluid flow is heterogeneous within and around the tumors, and not always in the outward direction. These values were not linked to the tumor size. Finally, we compare our flow velocity magnitudes and the direction of flow to a classical marker of vessel leakage and bulk fluid drainage, Evans blue. With these data, we validate its use as a marker of high and low IFF rates and IFF in the outward direction from the tumor border in implanted glioma models. These methods show, for the first time, the nature of interstitial fluid flow in models of glioma using a technique that is translatable to clinical and preclinical models currently using contrast-enhanced MRI.
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PMID:MRI analysis to map interstitial flow in the brain tumor microenvironment. 3045 43

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