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

Utilization of molecular biology techniques offers attractive options in nuclear medicine for improving cancer imaging and therapy with radiolabeled peptides. Two of these options include utilization of phage-panning to identify novel tumor-specific peptides or single chain antibodies and gene transfer techniques to increase the number of antigen/receptor sites expressed on malignant cells. Our group has focused on the latter approach for improving radiolabeled peptide imaging and therapy. The most widely used gene transfer vectors in clinical gene therapy trials include retrovirus, cationic lipids, and adenovirus. We have utilized adenovirus vectors for gene transfer because of their ability to accomplish efficient in vivo gene transfer. Adenovirus vectors encoding the genes for a variety of antigens/receptors (carcinoembryonic antigen, gastrin-releasing peptide receptor, somatostatin receptor subtype 2 (SSTr2)) have all shown that their expression is increased on cancer cells both in vitro and in vivo following adenovirus infection. Of particular interest has been the adenovirus encoding for SSTr2 (AdCMVSSTr2). Various radioisotopes have been attached to somatostatin analogues for imaging and therapy of SSTr2-positive tumors both clinically and in animal models. The use of these analogues in combination with AdCMVSSTr2 is a promising approach for improving the detection sensitivity and therapeutic efficacy of these radiolabeled peptides against solid tumors. In addition, we have proposed the use of SSTr2 as a marker for imaging the expression of another cancer therapeutic transgene (e.g. cytosine deaminase, thymidine kinase) encoded within the same vector. This would allow for non-invasive monitoring of gene delivery to tumor sites.
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PMID:Gene transfer strategies for improving radiolabeled peptide imaging and therapy. 1110 86

Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.
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PMID:Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35. 1177 3

Adenovirus-mediated suicide gene therapy may hold promise in the treatment of human cancer. We have developed a novel approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/TKrep) to deliver a cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion gene to tumors. The cytosine deaminase and herpes simplex virus-1 thymidine kinase suicide genes render malignant cells sensitive to specific pharmacological agents and, importantly, sensitize them to radiation. The Phase I study described here represents the first gene therapy trial in which a replication-competent virus was used to deliver a therapeutic gene to humans. The indication is local recurrence of prostate cancer after definitive radiation therapy. An escalating dose (10(10), 10(11), and 10(12) viral particles) of the Ad5-CD/TKrep virus was injected intraprostatically under transrectal ultrasound guidance into 16 patients in four cohorts. Two days later, patients were given 5-fluorocytosine and ganciclovir prodrug therapy for 1 (cohorts 1-3) or 2 (cohort 4) weeks. There were no dose-limiting toxicities, and the maximum tolerated dose of the Ad5-CD/TKrep vector was not defined. Ninety-four percent of the adverse events observed were mild or moderate (grade 1/2) in nature. Seven of 16 (44%) patients demonstrated a >or=25% decrease in serum prostate-specific antigen, and 3 of 16 (19%) patients demonstrated a >or=50% decrease in serum prostate-specific antigen. Transgene expression and tumor destruction at the injection site were confirmed by sextant needle biopsy of the prostate at 2 weeks. Two patients were negative for adenocarcinoma at 1 year follow-up. Although Ad5-CD/TKrep viral DNA could be detected in blood as far out as day 76, no infectious adenovirus was detected in patient serum or urine. Together, the results demonstrate that intraprostatic administration of the replication-competent Ad5-CD/TKrep virus followed by 2 weeks of 5-fluorocytosine and ganciclovir prodrug therapy can be safely applied to humans and is showing signs of biological activity.
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PMID:Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. 1220 48

Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present study, we examined the efficacy of adv/tk/GCV gene therapy in a syngeneic BT4C rat malignant glioma model, either as a single administration or given as three injections during three consecutive days. The effect of combined adv-mediated macrophage colony-stimulating factor (MCSF) and adv/tk gene transfer was also studied. BT4C malignant glioma cells were injected into the right corpus callosum of BDIX rats (n=112). Before gene therapy, the presence of tumors was verified by MRI. The rats were divided into eight groups as follows: group I (n=20) received a single adv/tk gene transfer (total dose 4x10(8) pfu) and GCV treatment for 14 days; group II (n=5) received the same gene transfer without GCV; group III (n=28) received three adv/tk injections (total dose 4x10(8) pfu) on three consecutive days and GCV for 14 days; group IV (n=5) received three similar adv/tk injections without GCV medication; group V (n=13) received three adv/MCSF injections (total dose 2x10(8) pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6x10(8) pfu) injections on three consecutive days followed by GCV medication; and group VII (n=12) the same treatment without GCV. Group VIII (n=17) consisted of wild-type BT4C malignant glioma tumors without any treatment. Treatment effect and tissue responses were characterized by general histology, immunohistochemistry, MRI, and survival of the study groups. The best treatment effect and survival was found in rats treated with adv/tk gene transfer once a day for three consecutive days (P<.05). No improvement of the treatment effect was seen after the combined adv/tk and adv/MCSF gene transfer compared with the repeated adv/tk gene transfer. The results show that 20% of the rats can be cured (survival >6 months) after optimized adv/tk gene therapy. It is concluded that repeated intratumoral administration of adv/tk is a promising approach for the treatment of malignant glioma tumors in vivo.
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PMID:Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model. 1238 30

Thyroid cancers are of special interest in gene therapy, since it is possible to direct gene expression specifically to the thyroid derived cells by using promoters with limited expression, and secondly, because destruction of the normal tissue by introduction of a toxic gene would have no important adverse effect. A variety of methods for gene delivery are available. Adenovirus is a well studied and widely used vector and is useful for targeting genes because it infects many cell types, including differentiated thyroid cancer and medullary thyroid cancer cells. Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12. Combinations of vectors expressing thymidine kinase and IL-12 under control of a strong but non-tissue specific CMV promoter effectively destroy a model anaplastic thyroid tumor in Wistar rats. Replicating adenoviruses, in contrast to the non-replicating form commonly used, have also been used to infect tumor cells and express P-53 protein, leading to apoptosis of tumor cells. Medullary thyroid cancer provides a target much like differentiated thyroid cancer because it is possible to address gene expression specifically to the medullary thyroid cells by the use of a modified calcitonin promoter. Animal models of this tumor are available in a mouse and Wag/Rij rat model. In the latter system, treatment with adenoviruses expressing genes under control of the modified calcitonin promoter and expressing thymidine kinase or IL-12 leads to destruction of growing medullary thyroid cancer tumors, destroy distant tumors after injection in one tumor, and cause induction of long lasting immunity to subsequent tumor development in the animals. There are many ongoing studies of gene therapy in humans using various genes such as thymidine kinase, IL-2, and now IL-12. Although none of these trials to date shows complete eradication of metastatic tumors in humans, there are reports showing distinctly that the viral mediated gene therapy approach can effectively destroy human tumors after in vivo administration. Tumors that have been treated include melanomas, glioblastomas, breast tumors, and prostate carcinomas. In the latter studies, it has been possible to show objective responses documented by a fall in serum PSA levels of 50% or more that are sustained for prolonged periods. Gene therapy using the adenoviral vectors appears to be safe in studies reported so far. A problem is prior or induced immunity to adenoviral proteins, but direct injection of the vector into a tumor nodule largely circumvents this problem. New genes and new vectors under development will certainly lead to the established use of these methods in the therapy of human thyroid carcinomas in the near future.
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PMID:Viral mediated gene therapy for the management of metastatic thyroid carcinoma. 1537 25

Chronic papillary conjunctivitis has been described following adenoviral conjunctivitis. It is unknown however, how long adenovirus is able to persist in the tear film and conjunctiva. To determine if adenovirus persists in the ocular surface following adenoviral conjunctivitis, 304 patients with a history of adenovirus conjunctivitis from whom an adenovirus had been isolated 10 years previously were sent a questionnaire regarding persistent or recurrent symptoms and were invited to attend. Patients were examined and samples of tears and conjunctival cells were collected from both eyes using tear film washes, filter paper, and swabs, the latter for virus isolation. Extracted DNA from the ocular samples was amplified using primers for herpes simplex virus (thymidine kinase) and adenovirus (hexon) genes. Adenovirus amplicons were sequenced and compared to original serotype. Thirty patients attended, 19 of whom had persistent papillary conjunctivitis. Evidence of adenovirus DNA was detected in 17 of 30 patients, 15 of whom also had evidence of a chronic papillary conjunctivitis. Adenovirus DNA was significantly associated with papillary conjunctivitis (P = 0.03). Adenovirus amplicons were successfully sequenced from six patients. Four patients harbored type 3 adenovirus, the same serotype with which they were infected originally 10 years previously. Two patients were infected originally with adenovirus serotype 3 but the current serotype was type 4. Infection of the ocular surface with adenovirus may predispose to the development of a persistent or recurrent conjunctivitis, the presence of which, appears to be associated with evidence of long term persistence of adenovirus DNA.
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PMID:Evidence for persistence of adenovirus in the tear film a decade following conjunctivitis. 1612 60

The Cre-loxP system has been routinely used for conditional activation and deletion of gene expression. However, the spatiotemporal manner of these events in the heart has not yet been defined by in vivo imaging. Adenovirus (1 x 10(9 )pfu) carrying the silent positron emission tomography (PET) reporter gene, herpes simplex virus type 1 thymidine kinase (HSV1-tk), was injected into the left ventricular wall of male transgenic mice (n=15) or FVB controls (n=8). Transgenic mice expressed Cre recombinase driven by a cardiac-specific alpha-myosin heavy chain (alpha-MHC) promoter. Following injection of the 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ([18F]-FHBG; 137+/-25 microCi) reporter probe, microPET imaging was used to assess the expression of HSV1-tk reporter gene in the myocardium. Two days following adenoviral injection, cardiac HSV1-tk gene activation resulted in tracer uptake of 3.20+/-0.51% ID/g for alpha-MHC-Cre and 0.05+/-0.02%ID/g for control mice (P<0.01). The in vivo results were confirmed by RT-PCR and Western blot analysis. Similar transfections were evaluated in both cardiac-specific and non-cardiac-specific cell lines. Enzyme activity showed a robust correlation (r2=0.82) between in vivo molecular imaging technique and traditional in vitro enzyme assays. With further development and validation, PET imaging will likely play an important role in the noninvasive, repetitive, and quantitative measurement of conditional gene activation in the future.
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PMID:Positron emission tomography imaging of conditional gene activation in the heart. 1754 39

Adenovirus vectors (Adv) are used widely in cancer gene therapy research. However, the clinical application of Adv currently is limited to local, intratumoral administration; systemic administration leads to redundant transgene expression in the liver and subsequent hepatotoxicity. Here we replaced the conventional cytomegalovirus (CMV) promoter of Adv with a tumor-specific telomere reverse transcriptase (TERT) promoter, to restrict expression of the Adv-transduced transgene to tumor tissue alone. We evaluated the therapeutic and side effects after systemic administration of Adv expressing herpes simplex virus thymidine kinase (Ad-HSVtk) in mice bearing Meth-A tumors. Although systemically injected CMV promoter-driven Ad-HSVtk lacked therapeutic effect, mice injected with 2x10(11) viral particles containing TERT promoter-driven Ad-HSVtk showed inhibited tumor growth and prolonged survival with minimal side effects. Our results suggest that Adv in which transgene expression is driven by the TERT promoter are a promising prototype of tumor-targeting vectors for effective and safe cancer gene therapy.
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PMID:TERT promoter-driven adenovirus vector for cancer gene therapy via systemic injection. 1770 36

Adenovirus (ADV)-mediated gene therapy with the thymidine kinase (TK) gene under control of the Rous sarcoma virus (RSV) promotor followed by the administration of acyclovir has been established in vitro for the treatment of ovarian cancer cells and has been used as the basis for intraperitoneal phase I clinical trials. It is unclear how long a significant degree of transgene translation can be expected after adenovirus-mediated TK transduction, where the transcriptional complex is localized in the nucleus in an episomal fashion and thus without stable integration. The possible interaction of acyclovir pretreatment with subsequent ADV-RSV-TK transduction also remains to be elucidated. Transgene expression and cell killing efficacy were analysed based on multiplicity of infection (MOI) and MTT assay. Anti-TK-antibody 1397 was used for immunocytochemistry and Western blot analysis of TK expression. After transduction with ADV-RSV-TK at an MOI of 66, TK translation increased strongly in MDH 2774 and OVCAR-3 cell lines during the initial 48 hours. Virtually constant expression of the TK transgene was observed by Western blot during eight days. Cell killing efficacy was increased by repeated daily administrations of acyclovir. Pretreatment with acyclovir did not result in significantly increased cell killing efficacy. No negative effect of acyclovir on ADV-RSV-TK transduction was observed. The at least week-long expression of the TK transgene with persistently increasing efficacy of cell killing after ADV-mediated tumor cell transduction provide a realistic basis for the development of multicycle ADV-mediated TK gene therapy approaches in the treatment of ovarian cancer. Continuous i.v. acyclovir treatment or daily oral acyclovir-prodrug therapy might simplify the substrate regimen for the TK gene.
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PMID:Persistent adenovirus-mediated thymidine kinase gene expression in ovarian cancer cells increases cell killing efficacy over time. 1903 80

We have generated a novel oncolytic Adenovirus (Ad), ColoAd1, with significantly increased potency ( approximately 100-fold) relative to its parent viruses, Ad11p and Ad3, or to the clinically tested oncolytic Ad, ONYX-015. Although this agent has a significant increase in its therapeutic window relative to ONYX-015 or its parent viruses, its ability to intervene and control virotherapy in treated patient is an important safety consideration for a novel biological therapy, such as ColoAd1. As there are no approved treatments for Ad infections, we sought to define whether antivirals being used to experimentally treat Ad infections (cidofovir (CDV), ribavirin) had any activity against ColoAd1. In addition, we incorporated a well-described pro-drug converting enzyme, the herpes simplex virus-thymidine kinase (HSV-TK) gene, into the viral genome to test whether the expression of this enzyme directly from the virus could be exploited as a safety valve for arresting the viral infection in the presence of the pro-drug, ganciclovir. Both the antiviral drug, CDV, and the incorporation of the pro-drug-converting TK enzyme were validated as effective approaches to controlling ColoAd1 infection, and this represents an important advancement in the development of ColoAd1 as an anticancer treatment.
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PMID:In vitro analysis of cidofovir and genetically engineered TK expression as potential approaches for the intervention of ColoAd1-based treatment of cancer. 1945 47


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