Class of 2007 Abstract / Objectives: To evaluate the efficacy of carmustine wafers over placebo plus surgery in the treatment of primary glioblastoma multiforme. Methods: Searches of MEDLINE (1966-2007), ASH (American Society of Hematology) abstracts, and ASCO (American Society of Clinical Oncology) abstracts were conducted to obtain clinical outcomes data (meta- analysis, randomized controlled studies) for the carmustine wafers or for the traditional form of therapy, surgical resection of glioblastoma multiforme. Serious adverse events associated with the chemotherapeutic agent were identified and their respective rates of incidence calculated. Three prospective randomized controlled trials were used to provide point estimates and distributions for the Monte Carlo simulation. Parameters used to populate the Markov model were derived from the extant primary literature for patients undergoing surgical resection with either carmustine or placebo for glioblastoma multiforme. The base case was a 50 year old male with primary glioma. Results: Findings indicated that carmustine wafers increased survival over placebo from 54.05 months [95% confidence interval 46.25-61.07] to 69.87 months [95% confidence interval 67.02-71.94]. Serious side effects such as intracranial hemorrhage, seizures, and infections were also taken into account in the decision analytic model. Conclusions: Carmustine wafers significantly increase survival in patients undergoing surgical resection for glioblastoma multiforme. Therefore, carmustine wafers should be used as an adjunct to surgery in these patients.

No description available.

Thesis (Ph.D.)--Kent State University, 2008. / Title from PDF t.p. (viewed Sept. 28, 2009). Advisor: Saikh Jaharul Haque. Keywords: GBM; Differentiation; Myc; Stat3; GFAP. Includes bibliographical references (p. 153-189).

No description available.

No description available.

No description available.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available online.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015. / Submitted by Raquel Viana (raquelviana@bce.unb.br) on 2016-05-31T21:08:28Z No. of bitstreams: 1 2015_ThaisTorquatoSales.pdf: 2906055 bytes, checksum: cffb10f33ad18864796f8568c7f00c30 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-05-31T21:08:56Z (GMT) No. of bitstreams: 1 2015_ThaisTorquatoSales.pdf: 2906055 bytes, checksum: cffb10f33ad18864796f8568c7f00c30 (MD5) / Made available in DSpace on 2016-05-31T21:08:56Z (GMT). No. of bitstreams: 1 2015_ThaisTorquatoSales.pdf: 2906055 bytes, checksum: cffb10f33ad18864796f8568c7f00c30 (MD5) / Glioblastoma multiforme (GBM) é o tipo mais comum de tumor cerebral primário em seres humanos adultos, representando aproximadamente 55% dos casos. O processo tumoral desenvolve-se de maneira agressiva e as opções terapêuticas são limitadas. O protocolo de tratamento padrão inclui radioterapia em combinação com temozolomida (TMZ), combinado com excisão cirúrgica quando possível. Apesar de alguns avanços no tratamento de GBM, o tempo de sobrevida dos pacientes diagnosticados com esse tipo de glioma é de aproximadamente 14,5 meses. A interferência de RNA (RNAi) é um mecanismo de silenciamento de genes e está entre as abordagens promissoras para a terapia do câncer. Assim, utilizou-se a metodologia de RNAi para supressão do canal de potássio Ether à go-go 1 (Eag1) em células de glioblastoma da linhagem U-87 MG. Este alvo molecular tem papel relevante na tumorigênese de vários tipos de câncer, auxiliando na proliferação celular e metástases. O estudo realizado na presente dissertação examinou o papel de Eag1 na viabilidade das células de glioma tratadas com TMZ. Inicialmente, realizaram-se ensaios experimentais com concentrações de TMZ (125, 250 ou 500 µM) e pontos temporais (24h, 48h, ou 72h). A viabilidade celular do glioma foi determinada via ensaio de 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). No ponto temporal de 72h e concentração de 250 µM, o fármaco TMZ diminuiu a viabilidade das células em aproximadamente 50%. Com base nesse resultado da curva dose-resposta, estabeleceu-se a concentração do quimioterápico para a execução dos ensaios seguintes. Testaram-se, também, os efeitos do bloqueador de canal de potássio astemizol (ATZ 2,5 µM, 5 µM e 10 µM) ou vetor de expressão de shRNA denominado pKv10.1-3 (0,2 μg) sobre a viabilidade do glioma nos tempos de 24, 48 e 72 horas. Este vetor expressa grampos curtos de RNA (shRNA) direcionados à sequência de RNAm de Eag1 5'-GTCCACTTGGTCCATGTCCAG-3'. Além disto, avaliou-se os efeitos causados por ATZ 5 µM ou por pKv10.1-3 (0,2μg) em combinação com TMZ 250 µM, no tempo de 72 horas. O tratamento com pKv10.1-3 potencializou, de maneira significativa, a redução na viabilidade celular causada por TMZ sobre células de glioma (77,2% versus 47,9%). Verificou-se, ainda, que a inibição de Eag1 por astemizol (5 µM) ou pKv10.1-3 aumenta a taxa de apoptose causada por TMZ, conforme ensaio de citometria de fluxo. pKv10.1-3 (0,2 µg) reduziu significativamente o conteúdo de RNAm de Eag1, para 0,57 vezes em relação ao valor observado no grupo controle negativo pScramble (0,2 µg), conforme resultado de RT-qPCR. Quanto à proteína Eag1, esta mostrou-se elevada nas células de glioblastoma humano da linhagem U-87 MG. Os tratamentos experimentais causaram redução do conteúdo desta proteína, detectada por imunocitoquímica. Portanto, os dados do presente estudo revelam que Eag1 desempenha papel na viabilidade das células de glioma, além disso, mostraram que a supressão desse canal potencializa a ação da TMZ em células U-87 MG de glioblastoma multiforme. / Glioblastoma multiforme (GBM) is the most common primary brain tumor in human adults, accounting for about 55% of cases. Tumorigenesis develops aggressively and the therapeutic alternatives remain limited. The standard treatment includes radiotherapy in association with chemotherapy with temozolomide (TMZ) and the surgical excision of tumor tissues. Despite some advances in GBM treatment, the survival time of patients diagnosed with GBM is nearly 14.5 months. RNA interference (RNAi) is a strategy for gene silencing considered a promising approach for cancer treatment. The present study used RNAi to suppress the Ether à go-go 1 (Eag1) potassium channel in U-87 MG glioblastoma cells. Eag1 is an oncological target which plays an important role in tumorigenesis of various cancers, improving cell growth and metastasis. The aim of this study was to examine the role of Eag1 in glioma cells treated with TMZ. First, we tested the effects of TMZ on glioma cell viability, examining drug concentrations (125, 250 and 500 µM) at three time points (24h, 48h and 72h). Cell viability was determined by the 3-(4,5)-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. At 72h and concentration of 250 µM, TMZ decreased the cell viability in about 50%. Based on this dose-response curve, the drug concentration for the following tests was set up. We also evaluated the effects of astemizole (ATZ, an Eag1channel blocker) at 2.5 µM, 5 µM and 10 µM or a shRNA expression vector named pKv10.1-3 (0.2 µg). This vector expresses short-hairpin RNA (shRNA) targeting the Eag1 mRNA sequence 5'-GTCCACTTGGTCCATGTCCAG-3'. Cell viability was determined at 24, 48 and 72 hours. In addition, we evaluated the effects caused by ATZ 5 µM or by pKv10.1-3 (0.2 µg) in association with TMZ 250 µM, at 72 hours. The vector pKv10.1-3 increased the effect of TMZ on glioma cells (77.2% vs. 47.9%). Also, the Eag1 inhibition by atemizole (5 µM) or pKv10.1-3 increased the apoptosis rate caused by TMZ, as determined by flow cytometry. pKv10.1-3 (0.2 µg) significantly decrease Eag1 mRNA content to 0.57 times in comparison with the value found in pScramble (0,2 µg) control group, as determined by RT-qPCR. Indeed, GBM cells present a high expression of Eag1 protein. The experimental treatments reduced this protein content, as revealed by immunocytochemistry results. In conclusion, the results of this study reinforce that Eag1 plays a role in glioma cell viability. In addition, they show the channel suppression improves TMZ effects on U-87 MG GBM cells.

Das Glioblastom ist mit 70 % aller Gliome der häufigste humane Hirntumor mit sehr ungünstiger Prognose. Es konnte gezeigt werden, dass das natürlich vorkommende Dipeptid Carnosin (β-Alanyl-L-histidin) die Proliferation von Glioblastomzellen inhibiert. Diese Wirkung des Carnosins konnte ebenfalls in vivo nachgewiesen werden. Da Carnosin auch einen Einfluss auf den ATP-Haushalt der Glioblastomzellen besitzt, war das Ziel dieser Arbeit einen Wirkungsort von Carnosin zu identifizieren, womit die ATP mindernden und proliferationshemmenden Eigenschaften erklärt werden können. Es wurde untersucht, ob Carnosin den Energiemetabolismus der Glioblastome beeinflusst. Dabei konnte mithilfe zellbiochemischer Methoden gezeigt werden, dass die untersuchten Zelllinien nicht von der Energieversorgung durch die mitochondriale oxidative Phosphorylierung abhängen, da sich weder Hemmung (KCN) noch Entkopplung (DNP) der Elektronentransportkette auf den zellulären ATP-Gehalt auswirkten. Carnosin hingegen verringerte den ATP-Spiegel dieser Zellen. Die Hemmung der Glykolyse durch Oxamat (LDH-Hemmung), bewirkte einen starken Abfall des intrazellulären ATP-Spiegels, worauf Carnosin keinen zusätzlichen Effekt mehr besaß. Carnosin konnte eine Wirkung auf die glykolytische ATP-Synthese zugesprochen werden. Da ein direkter, molekularer Wirkungsort auf diesem Weg nicht identifiziert werden konnte, wurde parallel untersucht, ob sich über Proteomanalysen der Glioblastomzelllinie T98G ein Wirkungsort, bzw. -mechanismus bestimmen lässt. Anhand der Methode der zweidimensionalen Gelelektrophorese (2D-GE) konnten 31 signifikant differenziell exprimierte Proteine detektiert werden, von denen 6 Proteine (VBP-1, OLA-1, TALDO 1, UROD, BAG-2, GRPEL1) über MALDI-TOF-Analysen identifiziert wurden. In Western-Blot-Analysen konnte ein Protein (VBP-1), neben T98G, auch in primären Glioblastomzelllinien als differenziell exprimiert nachgewiesen werden. Anhand der zellbiologischen und proteinbiochemischen Untersuchungen konnte einerseits eine Verbindung des Carnosins zum HIF1α-Signalweg und andererseits zur generellen posttranslationalen Peptidprozessierung hergestellt werden. Der direkte Nachweis eines Einflusses von Carnosin auf HIF1α wurde aber bisher nicht erbracht.