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)

Retrovirus vectors only integrate into the genome of dividing cells and can thus be used to selectively infect tumor cells in the adult rat brain. Gene delivery was assessed by using the retrovirus BAG vector, which bears the Escherichia coli lacZ gene under the MoMLV LTR promoter-enhancer element, and by histochemical staining for bacterial beta-galactosidase activity. Direct injection of this vector (90-900 cfu) into the adult rat brain, with or without prior inoculation of C6 glioma cells (2 x 10(5) cells) resulted in labeling of only a few cells as assessed 1 week later. When the psi 2-BAG packaging line was grafted into the brain, labeled psi 2-BAG cells could be found after 1 day, but not after 5 days, following grafting, suggesting that the grafted cells had been rejected and that no endogenous cells had integrated released vector, or that expression of lacZ had been turned off. In contrast, when the psi 2-BAG packaging line was grafted into a brain region, which had been inoculated previously with rat C6 glioma cells (2 x 10(5) cells), beta-galactosidase labeling of these tumor cells, identified by immunocytochemistry for glial fibrillary acidic protein and S100, could be demonstrated 10 days later. Thus, grafting of retrovirus packaging lines into adult brain provides a mean to infect tumor cells in situ. The grafted packaging cells may continue to release retrovirus particles for an extended period, thus infecting more cells at the stage of division appropriate for viral integration, as compared to inoculation of the virus alone. Grafting of retrovirus packaging cell lines could be used to selectively deliver "killer" or "suppressor" genes to tumor cells in the brain to curtail their growth.
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PMID:Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line. 212 47

We have previously demonstrated that retrovirus-mediated genes were transferred to mouse glioma cells in a meningeal gliomatosis model (Yamada et al.: Japanese Journal of Cancer Research 83:1244-1247, 1992). This retrovirus vector contains the Escherichia coli. beta-galactosidase (beta-gal) gene as a marker for integration of the lacZ gene, which is controlled by the SV40 early promoter. We investigated whether lacZ genes could be specifically controlled in mouse glioma cells by glial-specific promoters, including the 2.5 kb 5' flanking region of the mouse glial fibrillary acidic protein (GFAP) gene, the 1.3 kb 5' flanking region of the myelin basic protein (MBP) gene, and the 1.5 kb 5' flanking region of the myelin proteolipid protein (PLP) gene. Psi-2 packaging cells were transfected with each retrovirus vector (GFAP promoter-, MBP promoter-, and PLP promoter-lacZ) and the infectious virus particles were recovered from the supernatants. Blue staining for beta-gal was detected in various fibroblast, myeloma, and glioma cell lines transduced with the retrovirus BAG vector. On the other hand, blue staining was only detected in glioma cells after transduction with the lacZ gene-bearing retrovirus controlled by glial-specific promoters. The strongest promoter activity was detected after transduction with the retrovirus in which the MBP promoter controlled the lacZ gene. Mouse glioma cells transduced with retrovirus containing the MBP promoter directing the herpes simplex virus type 1 thymidine kinase (HTK) gene were extremely sensitive to ganciclovir, while the parental cells and cells transduced with retrovirus containing the lacZ gene were not sensitive to ganciclovir.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective expression of foreign genes in glioma cells: use of the mouse myelin basic protein gene promoter to direct toxic gene expression. 750 43

Murine RSV-M glioma cells were genetically labeled with a retroviral BAG vector carrying the Escherichia coli beta-galactosidase gene. The X-gal-positive stable cell line RSV-M/BAG was obtained by the FDG-FACS method. To examine the behavior of glioma cells in the brain, we homografted RSV-M/BAG cells into the brain of C3H/HeN mice as cell suspensions. Individual grafted glioma cells were easily detected by histochemical staining for B-galactosidase (beta-gal). Three days after grafting, the beta-gal-positive cells were mainly found in the subependymal zone of the lateral ventricle. In addition, some solitary labeled cells were found at locations distant from the injection sites. On the seventh day after implantation, tumor masses were observed and graft-derived glioma cells were migrating bilaterally along the fibers in the corpus callosum. Other labeled cells extended into the brain parenchyma via the perivascular (Virchow-Robin) spaces. Rapid and extensive migration of individual glioma cells was thus clearly demonstrated by intracerebral transplantation of RSV-M/BAG cells.
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PMID:Migration of genetically labeled glioma cells after implantation into murine brain. 793 73

Laser-induced fluorescence has been used to measure tissue levels of chloroaluminum sulfonated phthalocyanine in vivo in an implanted hamster cheek pouch carcinoma tumor model. The drug was excited at 610 nm via a pulsed nitrogen laser-pumped dye laser, and fluorescence intensity was monitored at 684 nm for up to 30 days after drug administration. Data were acquired noninvasively with high temporal and spatial resolution using the laser-induced fluorescence apparatus and were analyzed with a multicompartment pharmacokinetic model. In addition, our published data on a C6-BAG glioma rat brain tumor model were analyzed to illustrate the effect of different tumor models on the rates. The rates extracted from the pharmacokinetic model elucidate the mechanisms of drug uptake and retention in the cheek pouch and brain tumor models. The laser-induced fluorescence approach should lead to better drug dosimetry for photochemotherapy and allow quick characterization of the pharmacokinetics of new photosensitizers in tissue.
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PMID:Pharmacokinetics of a fluorescent drug using laser-induced fluorescence. 826 9

Intravenous gene transfer using recombinant retroviruses tends to suffer from a low infectious viral titer when conducted in vivo. This is, in part, caused by complement-mediated proteolytic inactivation of the retrovirus in human serum. However, if the retroviruses were directly injected into the brain, they might not be inactivated. Supernatant from amphotropic retrovirus-producing cells harboring the BAG vectors was incubated with sera or cerebrospinal fluid (CSF) of patients with gliomas or unrelated disorders. The retroviruses were severely inactivated in sera. However, no such inactivation was noted in CSF or fluid from the tumor bed of glioma patients. These data suggest that gene transfer using recombinant retroviruses could be done into the cavity after removal of the tumor in glioma patients.
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PMID:Infectious retrovirus is inactivated by serum but not by cerebrospinal fluid or fluid from tumor bed in patients with malignant glioma. 856 89

Both retro- and adenovirus-mediated gene therapy have been suggested as a novel approach to the treatment of malignant brain tumors. However, little information is available about the gene transfer efficiency in human malignant glioma in vivo. We compared the feasibility and safety of retrovirus- and adenovirus-mediated beta-galactosidase gene transfer in human malignant glioma. Beta-galactosidase gene was transferred to 10 patients with malignant glioma via a catheter inserted into the tumor. The catheter was left in place until the tumor resection. To maximize gene transfer efficiency, gene transfer vectors (BAG retroviruses, titer, 6 x 10(5) CFU; and adenoviruses, titer from 3 x 10(8) to 3 x 10(10) PFU) were injected into the tumor via the catheter once a day for three consecutive days, followed by tumor resection 1-2 days later. Tumor was resected in such a way that the catheter was still in place inside the tumor, which permitted accurate histological analysis of the transduced tumors. X-Gal staining for beta-galactosidase activity was used to study gene transfer efficiency and distribution of the marker gene. Beta-galactosidase gene transfer was well tolerated with both vectors. Except for two patients with clear increases in serum adenovirus antibody titers, no adverse tissue responses or systemic complications were noticed in any of the patients. Gene transfer was successful in all patients. Gene transfer efficiency varied between <0.01 and 4% with retroviruses and between <0.01 and 11% with adenoviruses. However, the transgene activity was not evenly distributed in the tumors. Both glioma cells and endothelium in the tumor blood vessels were transduced with retro- and adenovirus vectors. In conclusion, the safety and feasibility of in vivo gene transfer to human malignant glioma was established with retro- and adenovirus vectors. Adenoviruses were more efficient than retroviruses in achieving in vivo gene transfer. Transduction of endothelial cells may have important consequences for the proposed treatment strategies and selection of treatment genes. The results justify clinical gene therapy trials for malignant glioma.
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PMID:Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. 972 Oct 87

SPARC (secreted protein acidic and rich in cysteine)/BM40/Osteonectin is a matricellular protein with multiple effects on cell behaviour. In vitro, its major known functions are anti-adhesive and anti-proliferative, and it is associated with tissue remodelling and cancer in vivo. SPARC is overexpressed in many cancers, including breast cancer, and the effects of SPARC seem to be cell type-specific. To study the effects of SPARC on breast cancer, we transfected SPARC into the MDA-MB-231 BAG, human breast cancer cell line using the Tet-On inducible system. By western analysis, we found low background levels in the MDA-MB-231 BAG and clone X parental cells, and prominent induction of SPARC protein expression after doxycycline treatment in SPARC transfected clones X5, X21, X24 and X75. Induction of SPARC expression did not affect cell morphology or adhesiveness to collagens type I and IV, but it slowed the rate of proliferation in adherent cultures. Cell cycle analysis showed that SPARC slowed the progression to S phase. Doxycycline induction of SPARC also slowed the rate of monolayer wound closure in the cultured wound healing assay. Thymidine inhibition of proliferation abrogated this effect, confirming that it was due to anti-proliferation rather than inhibition of migration. Consistent with this, we were unable to detect any differences in migration and Matrigel outgrowth analysis of doxycycline-stimulated cells. We conclude that SPARC is inhibitory to human breast cancer cell proliferation, and does not stimulate migration, in contrast to its stimulatory effects reported for melanoma (proliferation and migration) and glioma (migration) cells. Similar growth repression by SPARC has been reported for ovarian cancer cells, and this may be a common feature among carcinomas.
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PMID:Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition. 1250 Sep 36

Bcl-2 associated athanogene 3 (BAG3) has a modular structure that contains a BAG domain, a WW domain, a proline-rich (PxxP) domain to mediate potential interactions with chaperons and other proteins that participate in more than one signal transduction. In search for novel interacting partners, the current study identified that 78kDa glucose-regulated protein (GRP78) was a novel partner interacting with BAG3. Interaction between GRP78 and BAG3 was confirmed by coimmunoprecipitation and glutathione S-transferase (GST) pulldown. We also identified that the ATPase domain of GRP78 and BAG domain of BAG3 mediated their interaction. Counterintuitive for a prosurvival protein, BAG3 was found to promote the cytotoxicity of breast cancer MCF7, thyroid cancer FRO and glioma U87 cells subjected to genotoxic stress. In addition, the current study demonstrated that BAG3 interfered with the formation of the antiapoptotic GRP78-procaspase-7 complex, which resulted in an increased genotoxic stress-induced cytotoxicity in cancer cells. Furthermore, overexpression of GRP78 significantly blocked the enhancing effects of BAG3 on activation of caspase-7 and induction of apoptosis by genotoxic stress. Overall, these results suggested that through direct interaction BAG3 could prevent the antiapoptotic effect of GRP78 upon genotoxic stress.
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PMID:BAG3 sensitizes cancer cells exposed to DNA damaging agents via direct interaction with GRP78. 2408 88

Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associates with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy.
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PMID:WW domain of BAG3 is required for the induction of autophagy in glioma cells. 2520 29