Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 gene plays a determinant role in radiation-induced cell death and its protein product is negatively regulated by MDM2. We investigated whether adenovirus-mediated modified p53 gene transfer, which blocks p53-MDM2 binding, is effective for radiation-induced cell death in hepatocellular carcinoma (HCC) at different MDM2 cellular levels. Human hepatocellular carcinoma cell lines expressing MDM2 at low levels (Huh7) and high levels (SK-Hep1) were used. Ad-p53 and Ad-p53vp are replication-deficient adenoviral vectors containing human wild-type or modified p53, respectively. The anti-tumor effect was highest for Ad-p53 + radiotherapy (RT) in the low-level MDM2 cells, whereas this effect was highest for Ad-p53vp + RT in the MDM2-overexpressing cells. In Huh-7 cells, Ad-p53 + RT decreased cell viability (32%) in vitro and inhibited tumor growth (enhancement factor, 1.86) in vivo. Additionally, p21 expression and apoptosis were increased. In contrast, in SK-Hep1 cells, Ad-p53vp + RT showed decreased cell viability (51%) in vitro and inhibition of tumor growth (enhancement factor, 3.07) in vivo. Caspase-3 expression and apoptosis were also increased. Adenovirus-expressing modified p53, which blocks p53-MDM2 binding, was effective in killing tumor cells overexpressing MDM2. Furthermore, the combination strategy for disruption of the p53-MDM2 interaction with RT demonstrated enhanced anti-tumor effects both in vitro and in vivo.
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PMID:Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma. 2251 May 92

Progress in vector design and an increased knowledge of mechanisms underlying tumor-induced immune suppression have led to a new and promising generation of Adenovirus (Ad)-based immunotherapies, which are discussed in this review. As vaccine vehicles Ad vectors (AdVs) have been clinically evaluated and proven safe, but a major limitation of the commonly used Ad5 serotype is neutralization by preexistent or rapidly induced immune responses. Genetic modifications in the Ad capsid can reduce intrinsic immunogenicity and facilitate escape from antibody-mediated neutralization. Further modification of the Ad hexon and fiber allows for liver and scavenger detargeting and selective targeting of, for example, dendritic cells. These next-generation Ad vaccines with enhanced efficacy are now becoming available for testing as tumor vaccines. In addition, AdVs encoding immune-modulating products may be used to convert the tumor microenvironment from immune-suppressive and proinvasive to proinflammatory, thus facilitating cell-mediated effector functions that can keep tumor growth and invasion in check. Oncolytic AdVs, that selectively replicate in tumor cells and induce an immunogenic form of cell death, can also be armed with immune-activating transgenes to amplify primed antitumor immune responses. These novel immunotherapy strategies, employing highly efficacious AdVs in optimized configurations, show great promise and warrant clinical exploration.
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PMID:Chapter six--Adenovirus-based immunotherapy of cancer: promises to keep. 2302 Dec 45

Colorectal carcinoma is one of the most frequent cancer diseases. For patients with this type of cancer, liver metastases are the main cause of death. Therefore, new therapeutic approaches are urgently needed to improve the outcomes. We found that both mRNA and protein levels of tissue inhibitor of metalloproteinase-3 (TIMP3) were decreased significantly in colorectal cancer tissue when compared with normal mucosa, suggesting that decrease of TIMP3 expression was correlated with malignant behavior of colorectal cancer. We evaluated the power of TIMP3, a new potent multiple functional molecule, as a biotheropeutic tool to treat cancer. Adenovirus-mediated TIMP3 transduction in CT26 colon cancer model demonstrated multiple effects to arrest cancer cell growth and induced massive apoptosis. Also, adenovirally transferred TIMP3 reduced adhesion, migration and invasion behaviors of CT26 cells in vitro. In vivo data showed that TIMP3 suppressed in vivo tumor growth and that liver metastasis was significantly reduced by TIMP3 transduction. This is the first systematic preclinical study to show that TIMP3 may be a potential molecular tool for colon cancer biological therapy.
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PMID:Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells. 2303 7

Bone morphogenetic protein 2 (BMP-2) is a member of the TGF-beta superfamily of signaling molecules, and has been shown to function as a tumor suppressor involved in development and progression of many malignancies. BMP-2 has previously been reported to be closely correlated with lung cancer. But, the role and molecular mechanisms of BMP-2 in lung cancer have not yet been comprehensively explained. The present study aims to elucidate the role of BMP-2 in growth and invasion of human lung adenocarcinoma (LAC) in vitro and in vivo. Adenovirus vector-mediated BMP-2 small hairpin RNA (shBMP-2) was used to transfect into A549 LAC cells to determine the functional relevance of BMP-2 and tumor growth and invasion in vitro and in vivo, and further investigate the expression levels of BMP-2, vascular endothelial growth factor (VEGF), matrix metallopeptidase-9 (MMP-9), phosphatidylinositol 3-kinase p85alpha (PI3Kp85alpha) and phosphorylated AKT (p-AKT). As a result, LAC cell proliferation and invasion were significantly diminished by knockdown of BMP-2 indicated by MTT and Transwell assays, and cell apoptosis and cycle arrest were markedly induced indicated by flow cytometry. When BMP-2 expression was knocked down, the expression of PI3Kp85alpha, p-AKT, VEGF and MMP-9 was also down-regulated in LAC cells. In addition, the tumor volumes in LAC subcutaneous nude mouse model treated with shBMP-2 were significantly smaller than those in control and ad-GFP groups. Taken together, our findings indicate that knockdown of BMP-2 inhibits growth and invasion of LAC cells possibly via blockade of the PI3K/AKT signaling pathway, and BMP-2 may be a potential therapeutic target for lung cancer.
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PMID:Adenovirus mediated knockdown of bone morphogenetic protein 2 inhibits human lung cancer growth and invasion in vitro and in vivo. 2329 87

Stathmin is the founding member of a family of microtubule-destabilizing proteins that have a critical role in the regulation of mitosis. Stathmin is expressed at high levels in breast cancer and its overexpression is linked to disease progression. Although there is a large body of evidence to support a role for stathmin in breast cancer progression, the validity of stathmin as a viable therapeutic target for breast cancer has not been investigated. Here, we used a bicistronic adenoviral vector that co-expresses green fluorescent protein and a ribozyme that targets stathmin messenger RNA in preclinical breast cancer models with different estrogen receptor (ER) status. We examined the effects of anti-stathmin ribozyme on the malignant phenotype of breast cancer cells in vitro and in xenograft models in vivo both as a single agent and in combination with chemotherapeutic agents. Adenovirus-mediated gene transfer of anti-stathmin ribozyme resulted in a dose-dependent inhibition of proliferation and clonogenicity associated with a G2/M arrest and increase in apoptosis in both ER-positive and ER-negative breast cancer cell lines. This inhibition was markedly enhanced when stathmin-inhibited breast cancer cells were exposed to low concentrations of taxol, which resulted in virtually complete loss of the malignant phenotype. Interestingly, breast cancer xenografts treated with low doses of anti-stathmin therapy and taxol showed regression in a majority of tumors, while some tumors stopped growing completely. In contrast, combination of anti-stathmin ribozyme and adriamycin resulted in only a modest inhibition of growth in vitro and in breast cancer xenografts in vivo. Although inhibition of tumor growth was observed in both the combination treatment groups compared with groups treated with single agent alone, combination of anti-stathmin therapy and taxol had a more profound inhibition of tumorigenicity, as both agents target the microtubule pathway. Clinically, these findings are highly relevant because taxol is one of the most active chemotherapeutic agents in breast cancer. These studies provide the proof-of-principle that stathmin provides an attractive molecular target, which could serve as a primary focus of novel approaches to breast cancer.
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PMID:Cell cycle inhibition therapy that targets stathmin in in vitro and in vivo models of breast cancer. 2361 50

Few options are available for treating patients with advanced prostate cancer (PC). As PC is a slow growing disease and accessible by ultrasound, gene therapy could provide a viable option for this neoplasm. Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating PC. We previously constructed a CRCA, cancer terminator virus (CTV), which showed efficacy both in vitro and in vivo for PC. The CTV was generated on a serotype 5-background (Ad.5-CTV) with infectivity depending on Coxsackie-Adenovirus Receptors (CARs). CARs are frequently reduced in many tumor types, including PCs thereby limiting effective Ad-mediated therapy. Using serotype chimerism, a novel CTV (Ad.5/3-CTV) was created by replacing the Ad.5 fiber knob with the Ad.3 fiber knob thereby facilitating infection in a CAR-independent manner. We evaluated Ad.5/3-CTV in comparison with Ad.5-CTV in low CAR human PC cells, demonstrating higher efficiency in inhibiting cell viability in vitro. Moreover, Ad.5/3-CTV potently suppressed in vivo tumor growth in a nude mouse xenograft model and in a spontaneously induced PC that develops in Hi-myc transgenic mice. Considering the significant responses in a Phase I clinical trial of a non-replicating Ad.5-mda-7 in advanced cancers, Ad.5/3-CTV may exert improved therapeutic benefit in a clinical setting.
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PMID:Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV). 2386 67

Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene- 7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3- mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.
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PMID:Chemoprevention gene therapy (CGT) of pancreatic cancer using perillyl alcohol and a novel chimeric serotype cancer terminator virus. 2423 57

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.
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PMID:Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma. 2498 Aug 21

Adenovirus vector-mediated herpes simplex virus-thymidine kinase/ganciclovir (ADV.tk/GCV) system is a promising approach for cancer gene therapy. This study aimed to investigate the anti-tumor efficacy and the underlying mechanisms of ADV.tk/GCV system in orthotopic hepatocellular carcinoma (HCC) model. A total of 132 female nude mice orthotopic HCC models were established and tumors were directly injected with ADV.tk (5.0 x 10(6) vector particles/kg) or saline solution, 24 h later the animals were intraperitoneally administrated by ganciclovir (30 mg/kg) or saline solution for 7 consecutive days. We observed that ADV.tk/GCV resulted in a significant regression of tumor growth and a significant prolongation of survival of the mice. At each given time point, the percentages of cleaved caspae-3, caspase-9 and TUNEL positive cells were significantly higher in the ADV.tk + GCV group than saline group (P < 0.005), while CD31 and VEGF staining were significantly less in ADV.tk + GCV group than in saline group (P < 0.005). In summary, ADV.tk/GCV system exhibits dramatic anti-tumor effects in orthotopic hepatocellular carcinoma model by promoting apoptosis and inhibiting angiogenesis, and is a promising treatment strategy for hepatic carcinoma.
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PMID:Adenovirus vector-mediated herpes simplex virus-thymidine kinase gene/ganciclovir system exhibits anti-tumor effects in an orthotopic hepatocellular carcinoma model. 2507 2

Adenovirus dodecahedron (Dd), a nanoparticulate proteinaceous biodegradable virus-like particle (VLP), was used as a vector for delivery of an oncogene inhibitor to hepatocellular carcinoma (HCC) rat orthotopic model. Initiation factor eIF4E is an oncogene with elevated expression in human cancers. Cell-impermeant eIF4E inhibitor, cap structure analog (cap) and anti-cancer antibiotic doxorubicin (Dox) were delivered as Dd conjugates. Dd-cap and Dd-dox inhibited cancer cell culture proliferation up to 50 and 84%, respectively, while with free Dox similar results could be obtained only at a 5 times higher concentration. In animal HCC model the combination treatment of Dd-cap/Dd-dox caused 40% inhibition of tumor growth. Importantly, the level of two pro-oncogenes, eIF4E and c-myc, was significantly diminished in tumor sections of treated rats. Attachment to Dd, a virus-like particle, permitted the first demonstration of cap analog intracellular delivery and resulted in improved doxorubicin delivery leading to statistically significant inhibition of HCC tumor growth.
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PMID:Virus-like particle-mediated intracellular delivery of mRNA cap analog with in vivo activity against hepatocellular carcinoma. 2510 83


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