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)

An E1B-defective adenovirus, named r2/Ad carrying the neo expression cassette, was constructed by homologous recombination. The construction, selection (using neomycin as a selective marker), and propagation of the recombinant virus was performed in human embryonic kidney 293 cells (HEK 293). An in vitro study demonstrated that this recombinant virus has the ability to replicate in and lyse some p53-deficient human tumor cells such as human glioma tumor cells (U251) and human bladder cells (EJ), but not in some cells with functional p53, such as human adenocarcinoma cells (A549) and human fibroblast cells (MRC-5). Also, based on the cytopathic effect (CPE), it was demonstrated, under identical conditions, that the U251 cells were more sensitive to r2/Ad replication than the EJ cells. In this paper, we report that r2/Ad could be very useful in studying the in vitro selective replication of E1B-defective adenovirus and has great potential in cancer gene therapy.
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PMID:Conditional replication of a recombinant adenovirus studied using neomycin as a selective marker. 1278 82

Statins, which have been introduced to the clinic for the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid (MA). MA is the precursor in the biosynthesis of isoprenoid compounds including cholesterol, dolichol and ubiquinone. Furthermore, mevalonate-derived prenyl groups enable precise cellular localization and function of many proteins such as Ras and Rho proteins. Therefore, besides lowering cholesterol level, statins exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival but also participate in the regulation of cell shape and motility. Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process. In preclinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics. The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity. The results of several clinical studies of statins in cancer patients including phase I, phase I/II, and phase II trials have been published. Although evaluation of the therapeutic efficacy is not the purpose of early clinical trials and all conclusions might be premature at this stage, some preliminary conclusions have already been drawn. The results of these studies do not show any significant therapeutic effects of statins in cancer patients. However, the results of one of these studies suggest that statins could effectively strengthen the therapeutic activity of some chemotherapeutics. This observation seems to agree with the results of preclinical studies. However, as toxic side effects of statins have been particularly evident in their combination with some other drugs great caution should be advised while planning clinical trials based on combination therapy including statins in cancer patients.
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PMID:Potential antitumor effects of statins (Review). 1296 86

The expression of the prion (PRNP) and prion like-doppel (PRND) genes and the presence of the proteins prion (PrP) and doppel (Dpl) were investigated in human gliomas. The PRNP and PRND expression profiles were evaluated by real-time reverse transcription-quantitative PCR in low- and high-grade astrocytomas, in glioblastoma-derived cell lines and in non-glial tumor specimens. The presence of PrP and Dpl proteins and their cellular localization were evaluated by Western blot and immunohistochemistry. High levels of PRNP expression were found in all tumoral samples studied. Unlike the non-tumoral controls, PRND was aberrantly expressed in glioblastoma multiforme and in two glioblastoma multiforme-derived cell lines, even in the absence of the PRND gene amplification. PRND expression was directly related to malignancy of the tumor: highest in glioblastoma multiforme, lower in anaplastic astrocytoma and even lower in the low-grade astrocytoma samples. High levels of PRND were also found in non-glial malignant tumor samples, such as gastric adenocarcinoma and anaplastic meningioma. Western blot analysis confirmed the PrP and Dpl expression, displaying variability in the electrophoretic patterns. Immunohistochemical analysis revealed a diffuse cytoplasmatic Dpl distribution in different astrocytic neoplastic cells, in infiltrating lymphocytes and in blood vessel endothelial cells. Of note, Dpl reactivity was different from that of the PrP, since PrP showed typical Golgi and membrane localised staining. Our findings suggest that the PRND gene might be a useful molecular marker in astrocytoma progression and in tumor grade definition. Understanding of the mechanisms of PRND increased expression might provide insight into the regulatory pathways of glioma development.
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PMID:Differential expression of the prion-like protein doppel gene (PRND) in astrocytomas: a new molecular marker potentially involved in tumor progression. 1527 17

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Previously, it has been shown that Indian hedgehog (Ihh) and its two signaling receptors patched (Ptc) and smoothened (Smo) are involved in the pathogenesis of chronic pancreatitis (CP) and PDAC. In the current study we analyzed the expression, distribution, and function of another component of this signaling pathway, the human hedgehog-interacting protein (Hip), in the normal pancreas, CP and PDAC utilizing real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR), immunohistochemistry, immunofluorescence, Hip siRNA transfection, cell growth assays, and cell cycle analysis. By QRT-PCR, Hip mRNA levels were fifteenfold and fourteenfold increased in CP (n = 22) and PDAC (n = 31) tissues, respectively, compared to normal pancreatic tissues (n=20) and correlated with glioma associated antigen (Gli1) but not Ptc or Protein kinase A (PKA) mRNA levels. Only SU-8686 and BxPC-3 pancreatic cancer cells expressed Hip mRNA, whereas expression was below the level of detection in the other six pancreatic cancer cell lines tested. As shown by immunohistochemistry, Hip was expressed in normal pancreatic tissues mainly in the cytoplasm of islet cells and in smooth muscle cells of blood vessels. In contrast, in CP and PDAC there was a different distribution and staining intensity within the islets. Moreover, Hip immunoreactivity was observed in the tubular complexes, PanIN 1-3 lesions, as well as in pancreatic cancer cells. Incubation of pancreatic cancer cell lines with recombinant Hip revealed a growth inhibitory effect in SU-8686 and Capan-1 pancreatic cancer cells and no effect on cell growth in the other tested cell lines. In addition, silencing of Hip expression using specific siRNA molecules increased the growth of SU-8686 cells. In conclusion, Hip is expressed in the normal pancreas, CP and PDAC tissues. The different pattern of Hip expression and abnormal localization in the diseased pancreas suggest that the enhanced activation of hedgehog signaling in CP and PDAC is-at least in part-due to the aberrant responsiveness and expression of Hip in these diseases.
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PMID:Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. 1575 13

In an attempt to assess the permeability of microvessels in the experimental brain tumor model, lanthanum ion (La3+) was used as a low-molecular weight electron microscopic probe. Rat glioma 9 L and adenocarcinoma ACL15 were transplanted to the brain and subflank of rats. The rats were then anesthetized sequentially perfused with saline, saline plus La3+ followed by a fixative in phosphate buffer. The brain and subcutaneous tumors were removed, further fixed, and processed for electron microscopy. La3 did not pass through the tight junctions of the normal cerebral endothelium. Similarly, La3+ did not penetrate the endothelial cell wall of the microvessels in the transplanted brain tumors. In contrast, extravasation of La3+ from the microvessels in the transplanted subcutaneous tumors was observed. The electron microscopy examination results indicate that the vesicular transport was a predominant mechanism in the penetration of La3+ through the endothelial cell wall. Since most chemotherapeutic agents similar as La3+ are of low molecular weight, we can suggest from the results of our present study that the blood tumor permeability of the anti-cancer agents in the rat model of brain glioma transplantation differs from that in the rat model of subcutaneous glioma transportation. In other words, our results indicate that when the subcutaneous glioma transplantation model is used in sensitivity tests of anti-cancer agents, it will possibly be very difficult to predict the anti-neoplastic effect in vivo.
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PMID:Blood tumor permeability of experimental brain tumor: an electron microscopic study using lanthanum. 1582 15

We have assessed the effect of exogenous human tumor necrosis factor alpha (hTNFalpha) in three human cancer cell lines; MDA-MB-361 (breast adenocarcinoma), HCT 116 (colon carcinoma) and 8-MG-BA (glioma). In vitro transfection of a plasmid containing hTNFalpha under the control of a hybrid promoter resulted in expression of hTNFalpha gene in all three cell lines and secretion into the culture medium was seen with MDA-MB-361 cells. Flow cytometric analysis showed a significant increase in apoptotic and necrotic cells in MDA-MB-361 and to a lesser extent in HCT 116 cells. Increased apoptosis was confirmed by an increase in pro-caspase 3 activation. No effects of hTNFalpha expression were seen in 8-MG-BA cells. Intratumoral delivery of the hTNFalpha expression plasmid into MDA-MB-361 tumor xenografts grown in nude mice caused hemorrhagic tumor necrosis. This strategy may be a simple and promising gene therapy approach to the treatment of some human tumors.
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PMID:Tumor targeted gene therapy with plasmid expressing human tumor necrosis factor alpha in vitro and in vivo. 1605 53

Although a significant negative prognostic factor, tumor hypoxia can be exploited for gene therapy. To maximize targeting within the tumor mass, we have developed synthetic gene promoters containing hypoxia-responsive elements (HREs) from the erythropoietin (Epo) gene as well as radiation-responsive CArG elements from the early growth response (Egr) 1 gene. Furthermore, to achieve high and sustained expression of the suicide gene herpes simplex virus thymidine kinase (HSVtk), our gene therapy vectors contain an expression amplification system, or 'molecular switch', based on Cre/loxP recombination. In human glioma and breast adenocarcinoma cells exposed to hypoxia and/or radiation, the HRE/CArG promoter rapidly activated Cre recombinase expression leading to selective and sustained HSVtk synthesis. Killing of transfected tumor cells was measured after incubation with the prodrug ganciclovir (GCV; converted by HSVtk into a cytotoxin). In vitro, higher and more selective GCV-mediated toxicity was achieved with the switch vectors, when compared with the same inducible promoters driving HSVtk expression directly. In tumor xenografts implanted in nude mice, the HRE/CArG-switch induced significant growth delay and tumor eradication. In conclusion, hypoxia- and radiation-activated 'molecular switch' vectors represent a promising strategy for both targeted and effective gene therapy of solid tumors.
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PMID:Hypoxia- and radiation-activated Cre/loxP 'molecular switch' vectors for gene therapy of cancer. 1630 3

Breast cancer is the most common cancer in women. Germline mutations in BRCA-1 and BRCA-2 significantly increase the risk of developing breast and ovarian cancers, and are also associated with an increased incidence of primary cancers at other sites. We report the case of a 46-year-old woman previously treated for ductal adenocarcinoma of the breast with BRCA-1 who subsequently was diagnosed with multicentric glioblastoma multiforme (GBM) in the right temporal and right occipital lobes. We briefly discuss the incidence of BRCA-1 mutations in breast cancer as well as other primary neoplasms and consider potential mechanisms shared in the pathogenesis of breast and glial tumors.
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PMID:Multicentric glioblastoma multiforme in a patient with BRCA-1 invasive breast cancer. 1695 68

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
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PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

Brother of the regulator of imprinted sites (BORIS) was previously described as a transcription factor for epigenetic reprogramming the expression of which is strictly confined to germ cells of adult testes but is aberrantly activated in the vast majority of neoplastic cells. Considering the critical role of BORIS in cancerogenesis and the fact that its expression pattern may preclude thymic tolerance, we generated DNA- and protein-based mouse BORIS antitumor vaccines using a non-DNA-binding version of the BORIS molecule. Clinical use of BORIS as a vaccine Ag would require that certain safety concerns be met. Specifically, administration of the functional BORIS protein would hypothetically pose a risk of BORIS accelerating the progression of cancer. To alleviate such safety concerns, we have developed vaccines based on the BORIS molecule lacking the DNA-binding zinc fingers domain. To enhance anti-BORIS cellular immune responses, we used a standard molecular adjuvant approach. It consisted of plasmids encoding murine IL-12 and IL-18 for a DNA-based vaccine and conventional Th1 type adjuvant, Quil A, for a protein-based vaccine. Both DNA- and protein-based vaccines induced Ag-specific CD4(+) T cell proliferation with Th1 and Th2 cytokine profiles, respectively. Protein-based, but not DNA-based, BORIS vaccine induced a significant level of Ab production in immunized animals. Importantly, potent anticancer CD8(+)-cytotoxic lymphocytes were generated after immunization with the DNA-based, but not protein-based, BORIS vaccine. These cytolytic responses were observed across a wide range of different mouse cancers including mammary adenocarcinoma, glioma, leukemia, and mastocytoma.
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PMID:Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites. 1718 97


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