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

Adenovirus (Ad) vectors are being intensively studied as vehicles for cancer gene therapy. We have been exploring the benefits of direct intratumoral injection of Ads expressing cytokines for immunotherapy. Our previous work demonstrated that therapy using a vector expressing interleukin-12 (AdmIL-12.1) produced regressions in approximately 80% of treated tumors supporting further preclinical investigations. Recent reports have shown that immunity to Ad can be a major limiting factor in Ad-mediated gene transfer. As most animal studies with Ad vectors have involved nonimmune hosts, it remains difficult to predict how effective these treatments will be in humans, where the majority of individuals have had previous exposure to Ad. To address this question, we compared the effectiveness of the AdmIL-12.1 cancer therapy in naive and Ad-immune mice. We found that both groups responded equally well to treatment and that the response to AdmIL-12.1 in both groups resulted in the generation of CTL reactive against tumor antigen indicating that antitumor immunity was achieved. Peak transgene expression in the tumor was only reduced by 2.4 fold in Ad-immune animals compared with nonimmune mice. It was also observed that in naive animals, the virus disseminated from the site of the tumor following injection and by 72 h substantial transgene expression was detected in peripheral organs, most notably the liver. Transgene expression in the liver of Ad-immune animals was reduced by greater than 1000-fold relative to that in naive mice. These results strongly support the clinical utility of Ad-based cancer gene therapy and suggest that Ad immunity may be advantageous in that it is not a complete block to gene transfer in the tumor and it greatly reduces virus dissemination.
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PMID:Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination. 941 13

Adenovirus mediated transfer of growth-inhibiting molecules, such as p53 shows promise as an effective method of suppressing the growth of cancer cells. As the basis for in vivo studies, we examined transfection efficiency using 15 human lung cancer cell lines that differ in their endogenous p53 status. When infected with an adenovirus expressing bacterial beta-galactosidase, the different cell lines showed different levels of beta-galactosidase activity. We found a correlation between the level of integrin alpha v beta 5, which is thought to be an adherence receptor for adenoviruses, and the expression level of the transferred gene, suggesting that gene expression is largely dependent on the infection efficiency. Growth inhibition was induced in all cell lines tested following infection with an adenovirus containing p53, regardless of the genetic status of their endogenous p53 provided a sufficient amount of p53 protein was expressed. Our results (1) confirm that the examination of the susceptibility of target cancer cells to an adenovirus is important when considering performing adenovirus-mediated gene transfer and for evaluating its therapeutic effects; and (2) suggest that the quantification of integrin alpha v beta 5 may be a good way of predicting the susceptibility of cells to adenoviral vectors.
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PMID:The levels of integrin alpha v beta 5 may predict the susceptibility to adenovirus-mediated gene transfer in human lung cancer cells. 961 56

Adenovirus(ADV) mediated thymidine kinase(TK) gene therapy followed by ganciclovir(GCV) administration is widely used in different types of cancer. ACV shares the same mechanism of selective cell killing in ADV/TK positive cells as GCV and can be used at 4.5 times higher doses in patients without significant side effects. An increased dose of TK substrate is associated with improved bystander effect and more efficient cell killing. Toxicity and cell killing efficacy were assessed using a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide(MTT) based assay in three ovarian cancer cell lines with different proliferation patterns. At the same concentration, equal or higher cell killing efficacy and bystander effect were observed using ACV rather than GCV. 2.5 and 5 times (25 micrograms/ml and 50 micrograms/ml) higher concentrations of ACV always resulted in more effective cell killing than GCV (10 micrograms/ml, P < 0.01). Our data indicate that replacing GCV with ACV in the ADV-TK gene therapy may increase the treatment effect without increasing toxicity.
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PMID:Improvement of gene therapy for ovarian cancer by using acyclovir instead of ganciclovir in adenovirus mediated thymidine kinase gene therapy. 961 10

Adenovirus (Ad) is used as a vector for gene delivery in therapies involving genetic disease, vascular disease, and cancer. The first step for efficient gene transfer is effective virus binding to the target cells. We have found that Ad-mediated gene delivery to multiple cell types is much less efficient compared to epithelial-derived cells. Low gene delivery to nonepithelial cell types was directly correlated to a deficiency of the cellular receptor which mediates Ad binding. To overcome this inefficiency we constructed a new virus, AdPK, that contains a heparin-binding domain that targets the virus to broadly expressed, heparan-containing cellular receptors. AdPK delivers genes to multiple cell types at markedly higher efficiencies than unmodified Ad. Viruses with enhanced attachment characteristics significantly improve gene transfer efficiency and may expand the tissues amenable to efficient Ad-mediated gene therapy.
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PMID:Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types. 963 23

Previous studies in experimental models have demonstrated that the transduction of human or murine melanoma cells with the co-stimulatory B7-1 molecule induces effective antitumor immune responses. In order to develop B7-1 gene transfer as a therapeutic tool in the clinical management of melanoma, efficient means of in vivo gene transfer must be used. To this end we evaluated in vitro and in vivo immune responses associated with adenoviral transduction of murine and human melanoma cells with B7-1. Adenovirus-mediated transduction of human and murine melanoma cells with B7-1 leads to high-level transgene expression in vitro and in vivo and does not affect MHC class I and II expression. Adenovirus-delivered B7-1 induced antitumor immune responses, on the basis of observations that human melanoma cells transduced to express human B7-1 were able to co-stimulate allogeneic and autologous T cells to proliferate and that murine melanoma K1735 cells transduced to express murine B7-1 were rejected by syngeneic, immunocompetent mice. By contrast, intratumoral injection of an adenovirus encoding murine B7-1 failed to eliminate established murine melanoma (K1735) despite high-level transgene expression in tumor cells. Potent T cell inhibitory factor(s) secreted by both K1735 cells and select human melanoma cells may contribute to the failure to achieve protection in this setting. Thus, immune inhibitory melanoma-derived factors need to be taken into account when considering the clinical use of B7-1 immunotherapy.
Cancer Immunol Immunother 1998 Jul
PMID:Adenoviral transduction of melanoma cells with B7-1: antitumor immunity and immunosuppressive factors. 969 Apr 57

Adenovirus-mediated transduction of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by ganciclovir is suspected to induce immune-mediated, systemic antitumor activities in the RM-1 mouse prostate cancer model (S. J. Hall et al., Int. J. Cancer, 70: 183-187, 1997). Although numerous investigators have also implied a role for the immune system in both local and systemic effects resulting from HSV-tk treatment, the candidate effector cell(s) mediating these activities are unknown. Fresh lymphocytes harvested from treated tumors (tumor-infiltrating lymphocytes) generated significant in vitro lytic activity against the parental cell line, RM-1, and an unrelated prostate cancer cell line. In vitro antibody and complement depletion of CD3+ T cells and natural killer (NK) cells from tumor-infiltrating lymphocytes indicated that NK cells were the dominant mediator of the observed tumor cell lysis. Concurrently, no cytotoxic T-cell activity was ascertained within splenocytes of treated mice. In vivo depletion of NK cells resulted in a 20% reduction in growth suppression within the primary tumor and complete abrogation of the inhibition of preestablished lung metastases. Depletion of T cells had no effect on either response. Here, we identify the presence of NK cells within adenovirus/HSV-tk- and ganciclovir-treated tumors, which serve to mediate both local and systemic antitumor activities in this model, and lay the mechanistic groundwork for further improvements in this gene therapy strategy.
Cancer Res 1998 Aug 01
PMID:Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer. 969 45

Adenovirus (AdV)-mediated gene expression of immune stimulators represents a valuable in vivo approach for gene therapy of human cancer. The expression level of the therapeutic gene is of crucial importance for the efficacy of this type of treatment. Entry of AdV is dependent on the primary adenovirus receptor CAR and the secondary AdV receptor identified earlier to be a member of the integrin family of surface molecules. We have analyzed 14 different human melanoma cell cultures from different stages together with one melanoma cell line for their AdV-mediated transduction and expression efficiency. Recombinant viruses at various concentrations were used for expression of the B7-1 costimulatory molecule under the control of different promoters and the expression levels of B7-1 were analyzed by flow cytometry. AdV-mediated IL-12 expression was measured using a commercial ELISA. Levels of transgene expression were compared with the expression levels of HCAR, the alpha(v)beta3 and alpha(v)beta5 integrins, and HLA class I. In 4 of 14 cell cultures tested, the presence of the primary virus receptor CAR was associated with the high transduction efficiency phenotype when using the B7-1- and IL-12-expressing viruses at a relatively low multiplicity of infection (MOI) of 50. Immunohistochemistry on cryosections from the original biopsies yielded a strong signal specific for CAR. In contrast, cell cultures expressing low or undetectable levels of CAR needed a 20- to 40-fold higher viral input to show comparable expression level of B7-1 or IL-12. Expression levels of the transgenes hardly varied when using different promoters and no association was observed with the presence or absence of HLA class I molecules or with the expression levels of integrins.
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PMID:The presence of human coxsackievirus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures. 982 35

Current therapy for glioma is suboptimal. The transfer of apoptosis genes to tumors constitutes one of the most promising strategies for cancer gene therapy. We have previously shown that massive apoptosis occurs when wild-type p53 or E2F-1 expression is induced in glioma. However, the mechanism of action and the efficiency in inducing apoptosis of these two proteins are not similar. Adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain wild-type p53 genotype or overexpress the p21 protein. The p16/Rb/E2F pathway is the most frequent target of genetic alterations in gliomas, and therefore constitutes a suitable target for gene therapy strategies. However, the transfer of either the p16 or Rb gene to glioma cells results in cytostatic effect. The E2F-1 protein is able to induce generalized apoptosis in gliomas independently of the p53, p16 or Rb status. In addition, p21- or p16-mediated growth arrest did not protect glioma cells from E2F-1-mediated apoptosis. The apoptotic molecule bax is induced in p53-mediated apoptosis, but bax is not induced in E2F-1-mediated apoptosis in glioma cells. Careful selection of patients may be necessary before designing therapeutic strategies using either p53 or E2F-1 as a therapeutic tools for glioma patients.
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PMID:Gene therapy for gliomas: p53 and E2F-1 proteins and the target of apoptosis. 986 90

Adenovirus (Ad) vectors are promising for gene therapy of glioma due to their ability to achieve efficient gene transfer upon intratumoral administration. Yet in this context, Ad mediates widespread gene transfer to both tumor and surrounding parenchyma. Ad entry is dependent upon the expression of fiber receptors, such as coxsackie/adenovirus receptor, and alpha(v) integrins on the target cells for binding and internalization, respectively. We hypothesized that the susceptibility of human gliomas to Ad would likely be heterogeneous due to variable expression of these receptors. It was found that established human glioma cell lines exhibited differential susceptibility to Ad-mediated gene transfer, which correlated directly with the level of radiolabeled Ad binding and with the expression of coxsackie/adenovirus receptor but not with the expression of alpha(v) integrins. To circumvent the lack of fiber receptors and to target Ad gene transfer specifically to tumor cells, we used a bispecific antibody conjugate to ablate Ad binding to fiber receptors and retarget binding to the epidermal growth factor receptor (EGFR), a tumor-associated marker negligibly expressed in normal, mitotically quiescent neural tissues. The results demonstrate that EGFR-targeted Ad gene transfer was EGFR specific and independent of fiber-fiber receptor interactions. Furthermore, EGFR targeting significantly enhanced Ad gene delivery to 7 of 12 established glioma cell lines and to 6 of 8 cultured primary gliomas. Interestingly, EGFR-targeted Ad gene transfer did not correlate with EGFR expression across cell lines, suggesting the importance of other factors. This study establishes that fiber receptor expression limits the utility of Ad vectors for gene transfer to glioma cells and suggests that targeting Ad via EGFR may prove valuable for tumor-specific gene transfer to high-grade gliomas. These findings have key relevance in the context of Ad vector-based approaches for glioma gene therapy.
Cancer Res 1998 Dec 15
PMID:Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer. 986 32

Adenovirus-mediated transduction of the herpes simplex thymidine kinase gene (HSV-tk) in conjunction with ganciclovir (GCV) has been shown to result in significant growth suppression and to enhance survival in a model of mouse prostate cancer. However, this therapeutic activity is not sustained, because in most cases tumors eventually regrow and ultimately cause the death of the host. Androgen ablation, an inducer of apoptosis in prostate cells which is used widely as palliative therapy in patients with prostate cancer, was combined with HSV-tk plus GCV using an androgen-sensitive mouse prostate cancer cell line. The combination of castration and HSV-tk plus GCV led to markedly enhanced tumor growth suppression in both subcutaneous and orthotopic models compared with either treatment alone and resulted in an enhanced survival in which combination-treated animals lived twice as long as controls in the subcutaneous model and over 50% longer than controls in the orthotopic model. Further analysis of apoptotic activity demonstrated high levels of apoptosis only in combined androgen ablation and HSV-tk plus GCV-treated tumors after 14 days of growth in an androgen-depleted environment and 8 days after HSV-tk plus GCV therapy. At this time, the apoptotic index, but not the percent of necrotic tissue, was significantly higher for combination therapy-treated tumors relative to control-treated tumors or either treatment alone. These data indicate that the therapeutic effects of androgen ablation and HSV-tk plus GCV are cooperative and that increased apoptosis may, in part, underlie these activities.
Cancer Gene Ther
PMID:Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer. 1007 64


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