Anti-proliferative effect of the gastrin-release peptide receptor antagonist RC-3095 plus temozolomide in experimental glioblastoma models (original) (raw)
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Gastrin-releasing peptide receptor content in human glioma and normal brain
Brain Research Bulletin, 2010
The gastrin-releasing peptide receptor (GRPR) has been put forward as a therapeutic target in brain tumors. Here we evaluated GRPR presence in glioma specimens from patients as well as in normal human brain samples. Sections of paraffin-embedded brain tumors and non-neoplastic control brain tissue were analyzed with immunohistochemistry for GRPR content. Digital image analysis revealed that 100% of glioma samples
2008
Federal do Rio Grande do Sul. A pesquisa teve suporte financeiro pelo projeto do CNPq 400839/2005-9, pela South American Office for Anticancer Drug Development-SOAD-e pelo Instituto do Câncer Infantil-ICI. O RC-3095 foi gentilmente cedido pela Zentaris ltda, Alemanha. 4 Agradecimentos Primeiramente gostaria de agradecer a Deus por colocar pessoas tão maravilhosas em meu caminho. Agradeço a oportunidade de realizar este estudo em um laboratório com pessoas muito dedicadas e inteligentes, sendo totalmente especiais. Principalmente agradeço ao meu orientador, Dr. Rafael Roesler que confiou e acreditou no meu trabalho, muito obrigada por tudo! Gostaria de agradecer às pessoas do Laboratório de Pesquisa em Câncer do Hospital de Clínicas de Porto Alegre por todo o apoio e amizade, em especial,
Effect of temozolomide on the U-118 glioma cell line
Oncology Letters, 2011
are the most lethal subtype of astrocytomas, with a mean patient survival rate of 12 months after diagnosis. The gold standard treatment of GBM, which includes surgery followed by the combination of radiotherapy and chemotherapy with temozolomide (TMZ), increases the survival rate to 14.6 months. The success of TMZ appears to be limited by the occurrence of chemoresistance that allows glioma cells to escape from death signaling pathways. However, the mechanism of TMZ action is yet to be clarified although some controversial results have been reported. Therefore, our aim was to evaluate the occurrence of apoptosis and autophagy in glioma cells treated with TMZ and to correlate TMZ action with the survival pathways Pi3K/ Akt and ERK1/2 MAP kinase. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. Apoptosis was studied by flow cytometry as well as by fluorescence confocal microscopy in order to evaluate the sub G0/G1 percentage of cells and chromatin condensation. The expression of the autophagy-associated protein, LC3, as well as Akt and ERK1/2 was performed by Western blotting. In TMZ-treated GBM cells the expression of LC3, the autophagy-associated protein was increased and only a reduced percentage of cells underwent apoptosis. In addition, we showed that the phosphorylation status of Pi3K/Akt and ERK1/2 MAP kinase was maintained during the treatment with TMZ, suggesting that glioma cells escape from TMZ-induced cell death due to these signaling pathways. The chemoresistance of U-118 cells to TMZ was partially eradicated when cells were simultaneously treated with specific inhibitors of Pi3K/Akt and ERK1/2 MAP kinase signaling pathways and TMZ. Therefore, we hypothesized that in order to induce glioma cell death it is essential to evaluate the activation of the survival pathways and establish a combined therapy using TMZ and inhibitors of those signaling pathways.
Neoplasia (New York, N.Y.), 2016
Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale f...
The strategy for enhancing temozolomide against malignant glioma
Frontiers in Oncology, 2012
A combined therapy of the alkylating agent temozolomide (TMZ) and radiotherapy is standard treatment, and it improves the survival of patients with newly diagnosed glioblastoma (GBM). The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) removes the most cytotoxic lesions generated by TMZ, O 6 -methylguanine, establishing MGMT as one of the most important DNA repair mechanisms of TMZ-induced DNA damage. Thus, the expression of MGMT, its activity, and its promoter methylation status are associated with the response of GBM to TMZ, confirming that MGMT promotes clinical resistance to TMZ. Previous studies have shown that a variety of drugs such as interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increased the sensitivity of TMZ through MGMT-dependent or MGMT-independent mechanisms. In this review, we describe drugs and promising molecules that influence the responsiveness of GBM to TMZ and discuss their putative mechanism of action. In MGMT-positive GBMs, drugs that modulate MGMT activity could enhance the therapeutic activity of TMZ. Thus, administration of these drugs as an adjunct to TMZ chemotherapy may have clinical applications in patients with malignant gliomas to improve the outcome.
Recent Approaches and Novel Therapeutic Targets in Human Glioma
Advances in Cancer Research & Treatment, 2013
Malignant gliomas are highly invasive primary brain tumors that are not known to metastasize outside the central nervous system (CNS). The median survival time of patients with glioma is only 6 months to 2 years depending on the variability in patient's condition, type of tumor and variable treatment parameters. In recent times, Gamma knife (GK) and temozolomide (TMZ) have showed a new dimension for the treatment of gliomas, even these modalities have not able to bring a paradigm shift in overall survival and morbidity. Despite the aggressive current therapeutic interventions such as surgery, radiotherapy and chemotherapy, improved therapeutic strategies/targets are greatly needed. Interactions between the tumor and its microenvironment are known to regulate malignancies and there is need to focus more research on these pathways in order to develop more reliable therapeutic strategies for the treatment of gliomas. It has also been shown that drug transporters are highly expressed by small population of most type of tumors, providing for a level of resistance which are relatively quiescent and show higher level of DNA repair, and a lowered ability to enter the apoptosis; can provide another therapeutic targets in most of the cancer types including gliomas. The alteration of miRNA expression profile in glioma has also been found to be associated with neoplastic agents, hence open a new direction for the treatment. Therefore, the present review has been focused on some of these new potential targets for therapeutic interventions in the prognosis and treatment of human glioma.