Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma is the most malignant primary brain tumor. Inhibition of angiogenesis is one potential strategy for treating this fatal hypervascular tumor. AGM-1470 (also called TNP-470), a novel, potent, fungus-derived inhibitor of angiogenesis, was tested on the growth of human glioblastoma cells in culture and on the growth of the tumor in nude mice. In nude mice with subrenally implanted U-87 MG glioblastomas, AGM-1470 significantly inhibited tumor growth (P < 0.01), and in nude mice with intracranial U-87 MG glioblastomas, AGM-1470 prolonged survival. In addition to its expected action as an angiogenesis inhibitor, AGM-1470 also directly inhibited U-87 MG cells in culture at concentrations similar to those that inhibited endothelial cells. The combined inhibition of glioblastoma cell mitosis and of glioblastoma-induced neovascularization suggests that AGM-1470 should be considered for further investigation in the treatment of this fatal tumor.
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PMID:AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. 805 85

Glioblastoma cells secrete transforming growth factor-beta (TGF-beta), which has a variety of immunosuppressive properties. We investigated the effect of irradiation TGF-beta secretion by malignant glioma cells. Three malignant glioma cell lines (T98G, A172, KG-1-C) were cultured and irradiated using 10 and 50 Gy Linac radiation. After further culture for 36 hours in serum-free culture medium, the supernatants were collected. The TGF-beta activity in the culture supernatants was determined using a specific bioassay. The levels of the active form and total TGF-beta in the supernatants from irradiated malignant glioma cells decreased compared to those from un-irradiated cells. However, since irradiation inhibited the growth of tumor cells, the amount of TGF-beta secretion per cell in irradiated cells tended to increase after irradiation. These results suggest that malignant glioma cells can still secrete TGF-beta and activate latent TGF-beta even after large dose irradiation, despite the inhibition of tumor growth.
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PMID:Effect of irradiation on transforming growth factor-beta secretion by malignant glioma cells. 919 90

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
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PMID:Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. 1498 53

Glioblastomas are the most common primary brain tumors in adults. These tumors exhibit a high degree of vascularization, and malignant progression from astrocytoma to glioblastoma is often accompanied by increased angiogenesis and the upregulation of vascular endothelial growth factor and its receptors. In this study, we investigated the in vivo antiangiogenic and antitumor effects of brain-specific angiogenesis inhibitor 1 (BAI1) using human glioblastoma cell lines. Glioblastoma cells were transduced with an adenoviral vector encoding BAI1 (AdBAI1), and Northern and Western blot analyses, respectively, demonstrated BAI1 mRNA and protein expression in the transduced tumor cells. Using an in vivo neovascularization assay, we found that angiogenesis surrounding AdBAI1-transduced glioblastoma cells transplanted into transparent skinfold chambers of SCID mice was significantly impaired compared to control treated cells. Additionally, in vivo inoculation with AdBAI1 of established subcutaneous or intracerebral transplanted tumors significantly impaired tumor growth and promoted increased mouse survival. Morphologically, the tumors exhibited signs of impaired angiogenesis, such as extensive necrosis and reduced intratumoral vascular density. Taken together, these data strongly indicate that BAI1 may be an excellent gene therapy candidate for the treatment of brain tumors, especially human glioblastomas.
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PMID:Antiangiogenic activity of BAI1 in vivo: implications for gene therapy of human glioblastomas. 1624 91

Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.
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PMID:Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. 1678 20

Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression.
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PMID:Primary glioblastomas express mesenchymal stem-like properties. 1696 31

Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12's mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer.
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PMID:Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. 1721 Jul 92

Glioblastoma (GBM), a highly aggressive (WHO grade IV) primary brain tumor, is refractory to traditional treatments, such as surgery, radiation or chemotherapy. This study aims at aiding in the design of more efficacious GBM therapies. We constructed a mathematical model for glioma and the immune system interactions, that may ensue upon direct intra-tumoral administration of ex vivo activated alloreactive cytotoxic-T-lymphocytes (aCTL). Our model encompasses considerations of the interactive dynamics of aCTL, tumor cells, major histocompatibility complex (MHC) class I and MHC class II molecules, as well as cytokines, such as TGF-beta and IFN-gamma, which dampen or increase the pro-inflammatory environment, respectively. Computer simulations were used for model verification and for retrieving putative treatment scenarios. The mathematical model successfully retrieved clinical trial results of efficacious aCTL immunotherapy for recurrent anaplastic oligodendroglioma and anaplastic astrocytoma (WHO grade III). It predicted that cellular adoptive immunotherapy failed in GBM because the administered dose was 20-fold lower than required for therapeutic efficacy. Model analysis suggests that GBM may be eradicated by new dose-intensive strategies, e.g., 3 x 10(8) aCTL every 4 days for small tumor burden, or 2 x 10(9) aCTL, infused every 5 days for larger tumor burden. Further analysis pinpoints crucial bio-markers relating to tumor growth rate, tumor size, and tumor sensitivity to the immune system, whose estimation enables regimen personalization. We propose that adoptive cellular immunotherapy was prematurely abandoned. It may prove efficacious for GBM, if dose intensity is augmented, as prescribed by the mathematical model. Re-initiation of clinical trials, using calculated individualized regimens for grade III-IV malignant glioma, is suggested.
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PMID:Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics. 1782 98

Integrin-linked kinase (ILK) was assesed as a therapeutic target in glioblastoma xenograft models through multiple endpoints including treatment related changes in the tumor microenvironment. Glioblastoma cell lines were tested in vitro for sensitivity toward the small-molecule inhibitors QLT0254 and QLT0267. Cell viability, cell cycle, and apoptosis were evaluated using MTT assay, flow cytometry, caspase activation, and DAPI staining. Western blotting and ELISA were used for protein analysis (ILK, PKB/Akt, VEGF, and HIF-1alpha). In vivo assessment of growth rate, cell proliferation, BrdUrd, blood vessel mass (CD31 labeling), vessel perfusion (Hoechst 33342), and hypoxia (EF-5) was done using U87MG glioblastoma xenografts in RAG2-M mice treated orally with QLT0267 (200 mg/kg q.d.). ILK inhibition in vitro with QLT0254 and QLT0267 resulted in decreased levels of phospho-PKB/Akt (Ser473), secreted VEGF, G2-M block, and apoptosis induction. Mice treated with QLT0267 exhibited significant delays in tumor growth (treated 213 mm3 versus control 549 mm3). In situ analysis of U87MG tumor cell proliferation from QLT0267-treated mice was significantly lower relative to untreated mice. Importantly, VEGF and HIF-1alpha expression decreased in QLT0267-treated tumors as did the percentage of blood vessel mass and numbers of Hoechst 33342 perfused tumor vessels compared with control tumors (35% versus 83%). ILK inhibition with novel small-molecule inhibitors leads to treatment-associated delays in tumor growth, decreased tumor angiogenesis, and functionality of tumor vasculature. The therapeutic effects of a selected ILK inhibitor (QLT0267) should be determined in the clinic in cancers that exhibit dysregulated ILK, such as PTEN-null glioblastomas.
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PMID:Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK). 1820 10

Glioblastoma multiforma (GBM) is one of the most aggressive tumors of the central nervous system. It can be represented by two components: a proliferative component with a mass effect on brain structures and an invasive component. GBM has a distinct pattern of spread showing a preferential growth in the white fiber direction for the invasive component. By using the architecture of white matter fibers, we propose a new model to simulate the growth of GBM. This architecture is estimated by diffusion tensor imaging in order to determine the preferred direction for the diffusion component. It is then coupled with a mechanical component. To set up our growth model, we make a brain atlas including brain structures with a distinct response to tumor aggressiveness, white fiber diffusion tensor information and elasticity. In this atlas, we introduce a virtual GBM with a mechanical component coupled with a diffusion component. These two components are complementary, and can be tuned independently. Then, we tune the parameter set of our model with an MRI patient. We have compared simulated growth (initialized with the MRI patient) with observed growth six months later. The average and the odd ratio of image difference between observed and simulated images are computed. Displacements of reference points are compared to those simulated by the model. The results of our simulation have shown a good correlation with tumor growth, as observed on an MRI patient. Different tumor aggressiveness can also be simulated by tuning additional parameters. This work has demonstrated that modeling the complex behavior of brain tumors is feasible and will account for further validation of this new conceptual approach.
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PMID:Biocomputing: numerical simulation of glioblastoma growth using diffusion tensor imaging. 1826 46


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