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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) are the most potent antigen presenting cells for inducing T-cell immune responses. The ability to grow human DCs from monocyte precursors provides an abundant source of these cells, which can be modified in vitro to present antigens. Re-administration of modified DCs to patients as vaccines has been shown in some cases to induce immune responses against cancer and infectious disease. Gene delivery to DCs provides an intracellular source of antigen for efficient and persistent loading of major histocompatibility complex (MHC) class I molecules. The aim of this study was to use monocyte-derived DCs (MD-DCs) from healthy donors to compare in vitro gene transfer, mediated by adenovirus, M. bovis Bacillus Calmette Guerin (BCG) and biolistic delivery. Efficiency of transfection and effect on DC phenotype, allostimulatory capacity and cytokine secretion was investigated. Adenovirus and BCG both showed a comparable ability to transfect MD-DCs, whereas the biolistic delivery by gene gun was unsuccessful in the reporter gene delivery. BCG transfection promoted MD-DC maturation as is apparent in the surface phenotype, allostimulatory capacity and cytokine secretion from cells. In comparison, adenovirus and biolistic delivery had a reduced effect on MD-DCs although enhancement of co-stimulatory and MHC molecule expression occurred in the cells of some donors. Both BCG and adenovirus represent useful vectors for gene transfer to human DCs. The effect of BCG on DC maturation may provide additional signals for the induction of antigen-specific T-cell responses.
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PMID:The response of human dendritic cells to recombinant adenovirus, recombinant Mycobacterium bovis Bacillus Calmette Guerin and biolistic methods of antigen delivery: different induction of contact-dependant and soluble signals. 1127 24

The aim of this study was to investigate therapeutic efficacy of adenovirus-mediated E1a gene therapy for ovarian cancer in vitro and in vivo. Recombinant replication-deficient adenoviral vectors were prepared by superinfection of 293 cells, and then purified. The efficacy of the adenovirus vector system to infect ovarian cells was tested using different multiplicity of infection (MOI) and different times (1-4) of Ad.RSVlacZ. SKOV-3 cells (10(3) per well) were infected once with 2 x 10(4) adenovirus. The cells were harvested and counted on different days for 7 days to generate the in vitro growth curve. Tumor-bearing mice were injected intraperitoneally with ovarian cancer cells and treated by intraperitoneal injection of 100 microl (2.5 x 10(8) PFU) viral solution containing either replication-deficient Ad.E1a(+); control virus Ad.E1a(-) which is the same adenovirus as Ad.E1a(+) except for E1a deletion, or just phosphate buffered solution. The transduction efficacy increased with higher MOI and reached a plateau at the 20:1 ratio. When Ad.E1a(+) was used to transduce the HER-2/neu overexpressing human ovarian cancer cell line SKOV-3, tumor cell growth in vitro was greatly inhibited by E1a transduction. Also, Ad.E1a+ greatly inhibited tumor growth of SKOV-3-bearing mice. Immunohistochemistry analysis indicated that Ad.E1a protein was expressed in tumor tissue and expression of HER-2/neu p185 protein was suppressed. Very strong beta-gal staining was detected in tumors, and beta-gal activity in small intestine, lung, heart, stomach, liver, and kidney was detected. No beta-gal activity was detected in the tumor and other organs in control mice injected with Ad.E1a(-) or PBS. Adenovirus-type 5 E1a gene can efficaciously inhibit HER-2/neu-overexpressing ovarian cancer, and this promising procedure could greatly benefit ovarian cancer patients with high expression of HER-2/neu.
Int J Gynecol Cancer
PMID:Adenovirus 5 E1a-mediated gene therapy for human ovarian cancer cells in vitro and in vivo. 1128 29

The epidermal growth factor receptor (EGFR) plays an important role in neoplastic growth control of malignant gliomas. We have demonstrated that radiation activates EGFR Tyr-phosphorylation (EGFR Tyr-P) and the proliferation of surviving human carcinoma cells, a likely mechanism of accelerated cellular repopulation, a major cytoprotective response after radiation. We now investigate the importance of radiation-induced activation of EGFR on the radiosensitivity of the human malignant glioma cells U-87 MG and U-373 MG. The function of EGFR was inhibited through a genetic approach of transducing cells with an Adenovirus (Ad) vector containing dominant-negative (DN) EGFR-CD533 (Ad-EGFR-CD533) at efficiencies of 85-90%. The resulting cells are referred to as U-87-EGFR-CD533 and U-373-EGFR-CD533. After irradiation at 2 Gy, both of the cell lines exhibited a mean 3-fold increase in EGFR Tyr-P. The expression of EGFR-CD533 completely inhibited the radiation-induced activation of EGFR. In clonogenic survival assays after a single radiation exposure, the radiation dose for a survival of 37% (D37) for U-87-EGFR-CD533 cells was 1.4- to 1.5-fold lower, relative to cells transduced with AdLacZ or untransduced U-87 MG cells. This effect was amplified with repeated radiation exposures (3 x 2 Gy) yielding a D37 ratio of 1.8-2.0. In clonogenic survival studies with U-373 MG cells, the radiosensitizing effect of EGFR-CD533 was similar. Furthermore, in vivo studies with U-87 MG xenografts confirmed the effect of EGFR-CD533 on tumor radiosensitization (dose enhancement ratio, 1.8). We conclude that inhibition of EGFR function via Ad-mediated gene transfer of EGFR-CD533 results in significant radiosensitization. As underlying mechanism, we suggest the disruption of a major cytoprotective response involving EGFR and its downstream effectors, such as mitogen-activated protein kinase. The experiments demonstrate for the first time that radiosensitization of malignant glioma cells through disruption of EGFR function may be achieved by genetic therapy approaches.
Clin Cancer Res 2001 Mar
PMID:Radiosensitization of malignant glioma cells through overexpression of dominant-negative epidermal growth factor receptor. 1129 65

Adenovirus is a widely used vector for cancer gene therapy because of its high infection efficiency and capacity for transgene expression in both dividing and nondividing cells. However, neutralisation of adenovirus by pre-existing antibodies can lead to inefficient delivery, and the wide tissue distribution of the coxsackie and adenovirus receptor (CAR, the primary receptor for adenovirus type 5) precludes target selectivity. These limitations have largely restricted therapeutic use of adenovirus to local or direct administration. A successful viral gene therapy vector would be protected from neutralising antibodies and exhibit a preferential tropism for target cells. We report here the development of a covalent coating and retargeting strategy using a multivalent hydrophilic polymer based on poly-[N-(2-hydroxypropyl)methacrylamide] (pHPMA). Incorporation of targeting ligands such as basic fibroblast growth factor and vascular endothelial growth factor on to the polymer-coated virus produces ligand-mediated, CAR-independent binding and uptake into cells bearing appropriate receptors. Retargeted virus is resistant to antibody neutralisation and can infect receptor-positive target cells selectively in mixed culture, and also in xenografts in vivo. Multivalent polymeric modification of adenovirus is an effective way of changing its tropism and interaction with the immune system. As a non-genetic one-step process, the technology is simple, versatile and should yield vectors with an improved safety profile.
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PMID:Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. 1131 9

Tumor-specific gene delivery is crucial to achieving successful effects in suicide gene therapy. Carcinoembryonic antigen (CEA) promoter has been widely used for this purpose, but the expression level of tumor-specific promoters such as CEA promoter is generally low. In the previous study, we used the Cre/loxP system and showed that LacZ expression by the CEA promoter was remarkably enhanced and maintained its specificity using the Cre/loxP regulation system. In this study, the Cre/loxP system was first applied to augmentation of selective expression of the cytosine deaminase (CD) gene as a suicide gene therapy in CEA-producing cells. The double infection with AxCEANCre expressing Cre recombinase under the control of the CEA promoter and AxCALNLCD expressing the CD gene under the control of the CAG promoter by the Cre switching system rendered CEA-producing tumor cells 13-fold more sensitive to 5-fluorocytosine (5-FC) compared with the single infection with AxCEACD expressing CD gene driven by the CEA promoter. The therapeutic efficacy of the enhanced CD/5-FC suicide gene therapy was evaluated in orthotopic implantation models of human gastric carcinoma. Adenovirus vectors (1 x 10(9) plaque-forming units) were administered i.p. into mice three times, and then 5-FC was administered i.p. for the next 10 days. Tumor volume and weight in mice treated with AxCEANCre and AxCALNLCD/5-FC were significantly reduced as compared with those in mice treated not only with Mock (AxCALacZ) but also with AxCEACD/5-FC (P < 0.0001). This beneficial effect on tumor burden was also reflected in the overall survival. The survival periods of the mice treated with AxCEANCre and AxCALNLCD/5-FC were longer than those of mice treated with Mock or AxCEACD/5-FC (P < 0.01). These results suggested that application of the Cre/loxP system could provide a new approach for enhanced selective suicide gene therapy of CD/5-FC for the treatment of advanced gastric carcinoma.
Cancer Res 2001 Aug 15
PMID:Carcinoembryonic antigen-specific suicide gene therapy of cytosine deaminase/5-fluorocytosine enhanced by the cre/loxP system in the orthotopic gastric carcinoma model. 1150 67

MUC1 protein is widely expressed on various human cancer cells and has a specific highly glycosylated core structure with multiple tandem repeats, which may include an immunogenic peptide sequence. The potency of MUC1 protein to induce human histocompatibility leukocyte antigen-class I-restricted cytotoxic T-lymphocyte (CTL) induction remains to be fully clarified in human beings. In the current study, we made MUC1-expressing human dendritic cells (DCs) using recombinant adenovirus vector. Adenovirus vector plasmid containing human MUC1 cDNA, pAdHM4-MUC1 was constructed using in vitro ligation with a shuttle vector, pHMCMV5. Adenovirus vector expressing MUC1 was generated by the transfection of PacI-digested recombinant vector plasmid into 293 cells. Human blood DCs were obtained from 7-day culture of monocytes with recombinant human (rh) granulocyte-macrophage (GM) colony-stimulating factor (CSF) and (rh)interleukin (IL)-4. Then, 1 x 10(6) DCs were incubated with viral supernatant at a multiplicity of infection of 200 for 24 h in the presence of rhGM-CSF and rhIL-4. Flow cytometric analysis showed that 30% to 40% of the transduced DCs expressed MUC I protein; by contrast, nontransduced or transduced DCs with mock virus expressed only small amounts of MUC1 protein. Adenovirus-mediated MUC1 gene transduction into DCs had no significant effect on DC surface marker expressions or functions such as mixed leukocyte reaction. Furthermore, MUCI-specific CD8+ CTLs could be induced from healthy donor blood lymphocytes using MUC1-expressing DCs as stimulators. These results suggested that MUC1 gene-transduced DCs are a functional and potent tool for triggering a CTL response against MUC1 cancer cells.
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PMID:Adenovirus-Mediated MUC1 gene transduction into human blood-derived dendritic cells. 1156 36

Adenovirus vectors expressing suicide genes represent a promising approach for cancer gene therapy. We wanted to determine whether the virion host shutoff (vhs) gene of herpes simplex virus could be used as a suicide gene for gene therapy of glioblastomas. The vhs gene was cloned downstream of the glial fibrillary acidic protein promoter to direct tissue-specific expression, and recombinant adenoviruses were generated in 293 cells. Viruses, which contained the vhs gene but did not express it, could readily be isolated; however, we were unable to plaque purify viruses that expressed vhs protein. We constructed a derivative of 293 cells expressing an antisense RNA to the vhs gene and used them to generate adenovirus vectors that express vhs protein. These cells were used to complement vhs-expressing adenoviruses through three rounds of plaque purification. This approach could be generalized to produce adenovirus vectors expressing other toxic transgenes.
Cancer Gene Ther 2001 Aug
PMID:Generation of adenoviruses encoding the herpes simplex virus vhs gene: a novel strategy to generate adenoviruses expressing genes toxic to producer cells. 1157 34

The potential therapeutic application of the gene transfer technology with adenovirus vectors seems to be enormous. Adenovirus vectors offer several advantages over other vectors, but several important limitations of adenovirus mediated gene transfer are also known. Great number of studies in inherited diseases and in different cancer therapy clinical trials have provided information of critical importance for design of efficient clinical protocols. Clinical trials have been extended to the treatment of many other diseases, too. There are about thirty currently active gene therapy protocols for the treatment only of HIV-1 infection in the USA. These programs aim to confer protective immunity against HIV-1 transmission to individuals who are in risk of infection, to develop preventive or therapeutic vaccines for patients with AIDS and other infectious diseases. Gene therapy represents one of the most important developments in oncology, however, before this can be realised as standard treatment the technical problems of gene delivery and higher safety must be overcome. The early--first and second generation--adenovirus vectors are now likely to be phased out for most diseases, and further experiments seem to be necessary. It might be change to the third generation or other, more modern vector application in clinical trials, as the helper dependent vectors. Almost all transcriptional unit is removed from the DNA of these vectors ("gutless vectors"), therefore they cannot reproduce, give higher gene expression and far less inflammatory. Despite the latest achievement reported in vector design it is not possible to predict yet to what extent and when gene therapy will be effective.
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PMID:[Adenovirus vectors and their clinical application in gene therapy]. 1169 63

Adenovirus E1A has been shown to suppress tumor growth and induce apoptosis in response to stress. To determine the mechanisms and regions of E1A that mediate these functions, we characterized stable transfectants of various E1A mutants in murine melanoma cells both in vitro and in vivo. Three E1A-mutant constructs were used in this study, those having a single deletion at either the NH(2)-terminal (dl1101) or conserved region 2 (CR2) domain (dl1108), or double deletions at both domains (dl0108). The in vitro study showed that the CR2 domain is required for E1A-mediated apoptosis, whereas the NH(2)-terminal domain is dispensable. The in vivo study showed that dl1101 and dl1108 were still able to suppress tumor growth, whereas dl0108 lost tumor-suppressive activity. By in situ immunohistostaining, we found that factor VIII, a marker for angiogenesis, was greatly suppressed in dl1108 transfectants that are resistant to apoptosis. Thus, inhibition of angiogenesis is involved in the NH(2)-terminal domain of E1A. In conclusion, we suggest that the NH(2)-terminal and CR2 domain of E1A mediate two distinct mechanisms of tumor suppression.
Cancer Res 2002 Jan 15
PMID:The NH(2)-terminal and conserved region 2 domains of adenovirus E1A mediate two distinct mechanisms of tumor suppression. 1180 76

5-Fluorouracil (5-FU) is a potent antimetabolite used for chemotherapy of gastrointestinal (GI), breast, and head and neck malignancies. Although clinical trials have been conducted, the poor therapeutic index of 5-FU has precluded its clinical use for a number of other tumor types. It is unclear whether this lack of utility is due to problems with drug delivery or inherent insensitivity. Adenovirus (Ad) vector-mediated cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy has the potential to overcome pharmacokinetic issues associated with systemic 5-FU and is particularly well suited to use with tumors in which local control is paramount, such as recurrent, localized prostate cancer and malignant gliomas. In this study, the in vitro response by a panel of human tumor cell lines derived from both GI (colon, pancreas) and non-GI (prostate, glioma) tumors to 5-FU and to AdCMVCD (an Ad encoding Escherichia coli CD)/5-FC was examined. Whereas the sensitivity (IC(50)) of individual cell lines to these agents varied, no significant difference in median IC(50) for either 5-FU or AdCMVCD/5-FC was evident for the four tumor types tested (P > 0.1). The relevant contributions of Ad gene transfer efficiency and inherent 5-FU sensitivity in determining response to AdCMVCD/5-FC were then assessed. Multiple linear regression analysis revealed that whereas both factors significantly contribute to the response, inherent 5-FU sensitivity was substantially more important (beta= 0.78 versus 0.48; P < 0.001). Finally, the therapeutic efficacy of a single intratumoral injection of AdCMVCD followed by systemic 5-FC was assessed in three intracranial C.B17 severe combined immunodeficient mouse models of human glioma. AdCMVCD/5-FC efficacy was specific, virus dose-dependent, and closely paralleled in vitro 5-FU and CD/5-FC sensitivity in two of three models tested. These results reveal that glioma cells are as sensitive as GI tumor cells to the antineoplastic effects of 5-FU, identify inherent 5-FU sensitivity as an important factor in determining CD/5-FC efficacy, and confirm previous findings in rat models that demonstrate the potential clinical utility of AdCMVCD/5-FC gene therapy for gliomas.
Cancer Res 2002 Feb 01
PMID:Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. 1183 May 32


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