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)

Gene-based therapeutic strategies for cancer mainly include augmentation of immunotherapeutic and chemotherapeutic approaches. In this study we report the design and functional assay of a novel bicistronic Moloney-based retroviral vector expressing human interleukin-2 (IL-2) and herpesvirus thymidine kinase (tk) through a cap-dependent translation and an internal ribosome entry site (IRES)-regulated translation, respectively. This construct has the potential for allowing combination of cytokine and suicide gene therapy, especially in areas such as the brain, composed of post-mitotic cells refractory to transduction by type C retroviral vectors. Accordingly, human glioma cells were used as targets for gene transfer after selecting a packaging cell clone that produced a reasonable titer of recombinant virus and expressed high levels of IL-2 and tk transcripts. Although transduction efficiency was reduced in glioma cells as compared with murine NIH 3T3 cells, transgene expression was effectively achieved. Transduced glioma cells were sensitive to ganciclovir and secreted around 1000 U/ml IL-2 in the culture supernatants. Simultaneous production of IL-2 and tk in vivo by genetically treated tumor cells would hopefully potentiate the effect of gangiclovir-induced metabolic suicide, possibly by boosting the immune response associated with tumor debulking or by amplifying the bystander response.
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PMID:Production and characterization of a bicistronic Moloney-based retroviral vector expressing human interleukin 2 and herpes simplex virus thymidine kinase for gene therapy of cancer. 981 72

Nerve growth factor (NGF) plays an important physiological role in differentiation and survival of various types of neurons. Glial cells and glial tumor cells synthesize multiple neurotrophic factors including NGF and secrete them into the surrounding environment; however, the mechanisms of NGF and the significance of NGF receptors have not been studied in detail. The C6 glioma cell line can synthesize NGF, respond to exogenous application of NGF and stimulate the expression of NGF receptor in an autocrine manner. In order to determine the significance of such an NGF autocrine system, the effects of exposure to exogenous NGF and deprivation of endogenous NGF were examined in a C6 glioma cell line in vitro. Exogenous NGF significantly inhibited maintenance of the cell number and thymidine incorporation. Morphological changes, including the formation of growth cones, outgrowth of processes and cellular hypertrophy, were observed, concurrently, indicating that exogenous NGF stimulated differentiation and thereby inhibited proliferation of the cells. Deprivation of endogenous NGF with anti-NGF antibody elicited a rapid decrease in cell number and thymidine incorporation, and led almost all of the cells to death within 8 days. The protein synthesis inhibitor, cycloheximide, strongly inhibited the death of NGF-deprived cells, suggesting the involvement of an active process requiring synthesis of suicide proteins. These findings imply that the NGF autocrine system plays a significant role in regulating the differentiation and survival of C6 glioma cells, similarly to neuronal cells.
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PMID:Control of proliferation and survival of C6 glioma cells with modification of the nerve growth factor autocrine system. 1022 32

To prevent neoplasia, cells of multicellular organisms activate cellular disposal programs such as apoptosis in response to deregulated oncogene expression, making the suppression of such programs an essential step for potentially neoplastic cells to become established as clinically relevant tumors. Since the mutation of ras proto-oncogenes, the most frequently mutated proto-oncogenes in human tumors, is very rare in some tumor types such as glioblastomas and gastric cancers, we hypothesized that mutated ras genes might activate a cell death program that cannot be overcome by these tumor types. Here we show that the expression of oncogenically mutated ras gene induces cellular degeneration accompanied by cytoplasmic vacuoles in human glioma and gastric cancer cell lines. Cells dying as a result of oncogenic Ras expression had relatively well-preserved nuclei that were negative for TUNEL staining. An immunocytochemical analysis demonstrated that the cytoplasmic vacuoles are derived mainly from lysosomes. This oncogenic Ras-induced cell death occurred in the absence of caspase activation, and was not inhibited by the overexpression of anti-apoptotic Bcl-2 protein. These observations suggested that oncogenic Ras-induced cell death is most consistent with a type of programmed cell death designated 'type 2 physiological cell death' or 'autophagic degeneration', and that this cell death is regulated by a molecular mechanism distinct from that of apoptosis. Our findings suggest a possible role for this non-apoptotic cell death in the prevention of neoplasia, and the activation of the non-apoptotic cell death program may become a potential cancer therapy complementing apoptosis-based therapies. In addition, the approach used in this study may be a valuable way to find genetically-regulated cell suicide programs that cannot be overcome by particular tumor types.
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PMID:Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. 1032 74

Major depression, opioid addiction, neurodegenerative diseases, and glial tumors are associated with disturbances of imidazoline receptors (IR) in the human brain. In depression, the level of a 45-kD IR protein (putative I1-IR) is increased in the brain of suicide victims (51%) and in platelets of depressed patients (40%). The density of platelet I1-IR ([125I]-p-iodoclonidine binding) is also increased in depression (135%). The 29/30-kD IR protein (putative I2B-IR) is downregulated (19%) in suicide victims in parallel with a reduction (40%) in the density of I2B-IR ([3H]idazoxan binding). Antidepressant drugs induce downregulation of 45-kD IR protein and I1-sites in platelets of depressed patients and upregulation of I2-sites in rat brain. The densities of I2B-IR and the related 29/30-kD IR protein are decreased (39% and 28%) in the brain of heroin addicts. The density of I2B-IR is increased in Alzheimer's disease (63%) and decreased in Huntington's disease (56%). Brain I2B-IR is not altered in Parkinson's disease. The level of I2-IR in glial tumors is increased (two-fivefold) in parallel with the abundance of the related 29/30-kD IR protein (39%), whereas the level of 45-kD IR protein is decreased (39%). The possible functional relevance of these findings in the context of the pathogenesis of these disorders remains to be elucidated.
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PMID:Imidazoline receptors and human brain disorders. 1041 44

Death ligand/receptor interactions and caspase activation mediate drug-induced apoptosis in certain cancer cells. The molecular mechanisms responsible for the chemoresistance of human malignant gliomas are largely unknown. Here, we report that malignant glioma cells co-express CD95 and CD95L without undergoing suicidal or fratricidal apoptosis. Glioma cells do not commit CD95/CD95L-dependent suicide or fratricide even when RNA and protein synthesis are inhibited. This is because ectopic expression of the viral caspase inhibitor, crm-A, or exposure to a neutralizing CD95L antibody, block apoptosis induced by exogenous CD95L but not cell death induced by cytotoxic concentrations of inhibitors of RNA and protein synthesis. Although some cytotoxic drugs enhance the expression of CD95 or CD95L, crm-A fails to block drug-induced cytotoxic and clonogenic cell death, suggesting that the drug-induced changes in CD95 and CD95L expression are epiphenomenal. There is also no difference in drug-induced apoptosis between crm-A-transfected and control cells as assessed by electron microscopy, in situ DNA end labeling and DNA fragmentation. Further, glioma cells selected for resistance to CD95L do not acquire cross-resistance to chemotherapy. However, the broad spectrum caspase inhibitor, ZVAD-fmk, inhibits drug-induced cytotoxic cell death, suggesting a role of crm-A-insensitive caspases in drug-induced apoptosis of glioma cells. Thus, drug resistance of malignant glioma cells may involve deficiencies in two interrelated pathways that mediate death in order tumor cell types: (i) death ligand/receptor signalling; and (ii) caspase activation.
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PMID:Death ligand/receptor-independent caspase activation mediates drug-induced cytotoxic cell death in human malignant glioma cells. 1049 Aug 41

Apoptosis is a physiological process wherein the cell initiates a sequence of events culminating in the fragmentation of its DNA, nuclear collapse, and finally disintegration of the cell into small, membrane-bound apoptotic bodies. Expression of Fas (APO-1, CD95) Receptor (FasR) and programmed or active cell (PCD) death was studied in childhood astrocytomas (ASTRs) with varying stages of malignancy, including pilocytic ASTR, low grade ASTR, anaplastic ASTR, and glioblastoma multiforme (GBM). The great majority of childhood glial tumors, particularly ASTRs express FasR whereas normal cells in the central nervous system (CNS) do not. FasR represents a transmembrane glycoprotein which belongs to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily. Apoptosis within ASTRs is triggered by the binding of FasR to its natural ligand (FasL) or by cross-linking with antibodies developed against FasR. Presence of FasL was also detected in childhood glial tumors. The expression of both FasR and FasL was also observed within the same ASTRs. Therefore, spontaneous, IP regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in childhood glial tumors. During a systematic, immunocytochemical screening of 42 childhood ASTRs tissues divided according to WHO classification: 6 WHO grade I or pilocytic ASTRs; 14 WHO grade II or low grade ASTRs; 16 WHO grade III or anaplastic ASTRs and 6 WHO grade IV or glioblastoma multiforme (GBM), we detected strong expression (intensity of staining: "A"--the highest possible; number of stained cells: +2 to +4, between 20% to 90%) of FasR, employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. FasR was present on 70% to 90% of tumor cells in pilocytic ASTRs, in 50% to 60% of the tumor cells in low grade ASTRs, in between 30% and 40% of the tumor cells in anaplastic ASTRs, and in between 20% to 35% of GBM cells. The panel of normal tissues employed as positive and negative tissue controls demonstrated presence of FasR in the prenatal thymus, mature tonsils and colonic epithelium. The use of a sensitive, indirect, six step immunoperoxidase or alkaline phosphatase conjugated streptavidin-biotin antigen detection technique provided excellent immunocytochemical results. A broad spectrum of neoplastic cells have been identified to express FasR: 1) carcinomas of epithelial origin, such as breast (ductal invasive, lobular invasive, mucinous), renal cell, gastric, colorectal, endometrial, prostate, pancreas, hepatocellular and large cell and squamous cell lung carcinomas: 2) non-epithelial neoplasms such as B cell mediastinal B cell and nodal non-Hodgkin's lymphomas large granular lymphocytic leukemia of T or NK cell origin malignant fibrous histiocytoma, malignant mesothelioma, leiomyosarcoma, epitheloid sarcoma and alveolar soft part sarcoma, as well as melanomas. Flow cytometry studies have also detected FasR expression on cells of adult T cell, and hairy cell leukemias, as well as in chronic B cell lymphocytic leukemia (BCLL). The coexpression of both FasR and FasL on several malignant cell types may represent an effective mechanism of tumor escape from the cellular immunological response of the host. It has been well established that brain tumors and melanomas produce their autocrine FasL, and even become capable of switching the signal transduction associated with FasL-FasR coupling from the PCD pathway to a tumor growth, proliferative pathway. It seems that the therapeutical use of FasR-FasL (main apoptotic pathway) may represent a new and exciting type of immunotherapy in the treatment of primary childhood glial tumors.
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PMID:Fas (Apo-1, CD95) receptor expression in childhood astrocytomas. Is it a marker of the major apoptotic pathway or a signaling receptor for immune escape of neoplastic cells? 1058 78

Central nervous system (CNS) tumors are the most common solid neoplasms in children. Medulloblastomas (MEDs) resemble embryonic neuroectodermal stem cells and their immature, uncommitted neuronal and glial progeny. Apoptosis is a basic physiological process wherein the cell initiates a sequence of events culminating in the fragmentation of its DNA, nuclear collapse, and finally, disintegration of the cell into small, membrane-bound apoptotic bodies. Expression of Fas (APO-1, CD95) receptor (FasR) and programmed or active cell death (PCD) was studied in childhood MEDs with varying stages of malignancy, and cell differentiation features. The majority of neoplastically transformed, neuroectodermal in origin cells, particularly in MEDs, express FasR, whereas normal cells in the CNS do not. FasR is a transmembrane glycoprotein, which belongs to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily. Apoptosis within childhood PNETs/MEDs is triggered by the binding of FasR to its natural ligand (FasL) or by cross-linking with anti-section i FasR antibodies. The resence of FasL has also been detected in childhood glial tumors. Therefore, a spontaneous, cellular immunophenotype (IP) regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in childhood brain tumors during neoplastic growth and progression. During our systematic immunocytochemical screening, we employed formalin fixed, paraffin-wax embedded tissue sections, as well as frozen sections of 34 primary human childhood PNETs/MEDs. The use of a sensitive, indirect, six step immunoperoxidase or alkaline phosphatase conjugated streptavidin-biotin antigen detection technique, modified by us, provided excellent immunocyto-chemical results. A systematic observation of the presence of apoptosis related markers (especially FasR) and cells in PCD was carried out. A strong expression (intensity of staining: "A"-the highest possible; number of stained neoplastic cells: +3 to +4, between 50% to 90%) of FasR, was detected employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. The panel of normal tissues employed as positive and negative tissue controls demonstrated presence of FasR in the prenatal thymus, mature tonsils and colon epithelium. Certainly, the coexpression of FasR, FasL, and other PCD-related proteins have also been reported in other human malignancies: breast cancer, colorectal carcinomas, large granular lymphocytic leukemia of T or NK cell origin, melanomas, lung, prostate, pancreas, and hepatocellular carcinomas. The coexpression of both FasR and FasL on several neoplastic cell types may represent an effective mechanism for tumor escape of the cellular immunological response of the host. It has been well established that brain tumors and melanomas produce their autocrine FasL, and even become capable of switching their signal transduction from the PCD pathway to a tumor growth, proliferative pathway. It seems that the therapeutical use of FasR-FasL (main apoptotic pathway) represents a new and exciting immunotherapeutical possibility in the treatment of primary childhood neuroectodermal tumors.
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PMID:Fas (APO-1, CD95) receptor expression and new options for immunotherapy in childhood medulloblastomas. 1065 26

Recent development of therapeutic modalities in neurosurgery has brought about dramatic improvement for prognosis of brain tumors. Nevertheless, malignant glioma is one of the most formidable neoplasms in humans. According to a report by the Committee of Brain Tumor Registry of Japan, five-year relative survival rate of malignant gliomas is less than 10%. Malignant gliomas grow aggressively infiltrating into the surrounding normal brain tissue. So that total surgical resection is impossible. The tumors respond to radiation and chemotherapy, however, the efficiency has sustained transiently. The advert of new strategies for the treatment of malignant gliomas has long been awaited. We have developed a cytokine gene therapy for malignant glioma since about 10 years ago. Here, we introduce both suicide gene therapies and immune gene therapies including our case(IFN-beta gene therapy).
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PMID:[Perspectives on postgenome medicine: Gene therapy for brain tumors]. 1119 66

Cancer suicide gene therapy affords the prospect of using the most optimal genes available because the source of the therapeutic gene is often irrelevant. Currently, there are numerous preclinical and clinical trials to develop tumor ablative therapies that use viral, yeast, or bacterial genes. One such gene, the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) is widely used as a suicide gene in combination with ganciclovir. In the study reported here, a restricted set of random sequences (semi-random) was introduced into the active site of HSV-1 TK, and the resulting variants were selected on the basis of their ability to confer increased ganciclovir or acyclovir sensitivity to Escherichia coli. Sequence analysis demonstrated that functional mutants contained three to five amino acid substitutions that are unique and novel combinations. On the basis of enzyme assay results, three mutants were identified for further analysis in vitro. These three mutants conferred substantial increased sensitivity to both ganciclovir and acyclovir when compared with IC50s of wild-type TK expressing rat C6 glioma cells. One mutant, SR39, was further evaluated in a xenograft tumor model in nude mice. Expression of SR39 in tumors was shown to prevent tumor growth at prodrug dosages that did not affect wild-type HSV-1 TK-expressing tumors. The use of any of these mutants as a suicide gene should provide a more effective and safer alternative to wild-type TK, because lower, less immunosuppressive doses of ganciclovir will be necessary for tumor ablation, and the use of acyclovir may now be possible.
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PMID:Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. 1130 82

To date, only few preclinical protocols on liposomal suicide gene transfer in tumors have been published, none of which directly compared viral to liposomal vectors in terms of immunoreactivity and efficacy. We thus studied the neuropathological alterations in 80 rats being treated for glioblastoma using liposomal and, for comparison, adenoviral and retroviral suicide gene transfer approaches to identify vector-associated efficacy and toxicity for further clinical studies. 62 rats served as controls. F98 tumors were established in Fisher rats and transfected in vivo with the thymidine kinase gene of herpes simplex virus (HSVtk) by a single intratumoral application and an implanted intratumoral continuous delivery system. Three days later ganciclovir was given intraperitoneally for 14 days. The animals were sacrificed 17 days post completed gene transfer. Brains were examined histologically and immunohistochemically using markers for immunocompetent cells. Ten animals showed complete tumor regression; they all belonged to the liposomal and adenoviral groups. In 6 of 10 experimental groups considerable numbers of lymphocytes along the margins of the regression cavities could be observed. Control animals of the liposomal and adenoviral groups showed only little lymphocytic infiltration, underlining the minimal immunogenicity of these carriers. In contrast, the retroviral control group featured a high lymphocyte infiltration. In summary, this study indicates that, in terms of both efficacy and immunoreaction, liposomes are as appropriate as adenoviruses in the treatment of rat glial tumors using suicide gene transfer strategies.
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PMID:Short-term neuropathological aspects of in vivo suicide gene transfer to the F98 rat glioblastoma using liposomal and viral vectors. 1151 Sep 63


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