Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell fusion experiments have predicted the existence of cancer metastasis suppressor genes. The E1a gene of Adenovirus 2 has been demonstrated to suppress c-Ha-ras induction of experimental metastatic potential in rat embryo fibroblasts. Another approach to the identification of candidate metastasis suppressor genes has utilized differential or subtraction hybridizations to clone genes which are downregulated as cells become highly metastatic. To date, three such genes have been identified: nm23, WDNM1, and fibronectin. With regard to nm23, downregulation of nm23 RNA levels in high metastatic potential cells has been demonstrated in a wide variety of rodent metastasis systems, including K-1735 murine melanoma cell lines, nitrosomethylurea-induced rat mammary tumors, MMTV-induced mouse mammary tumors, and ras +/- E1a transfected rat embryo fibroblasts. Whether the expression of the nm23 gene, and other down-regulated genes in tumor metastasis, correlates with changes in metastatic potential, or actually has suppressive activity, will require transfection experiments.
Invasion Metastasis 1989
PMID:Search for metastasis suppressor genes. 253 85

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Most patients have obvious metastases or locally advanced disease at the time of presentation. Surgical resection does not significantly change the clinical outcome. Combination chemotherapy induces a partial response but overall survival remains low. The aim of this study was to evaluate the feasibility of adenovirus-mediated suicide gene transduction as a therapeutic approach for pancreatic cancer. A cell line was established from a murine pancreatic ductal adenocarcinoma and intrahepatic tumors were generated by inoculation of pancreatic cancer cells into the left lateral liver lobe. Transduction efficiency was characterized in vitro and in vivo. Intrahepatic tumors were treated by intratumoral adenovirus injection in combination with intraperitoneal administration of ganciclovir. Adenovirus-mediated herpes simplex virus (HSV)-thymidine kinase (tk) gene expression followed by ganciclovir treatment was highly efficient in inhibiting pancreatic cancer cell proliferation in vitro. The proliferation of nontransduced cells was significantly reduced in the presence of HSV-tk expressing cells. Intrahepatic inoculation of pancreatic cancer cells leads to successful formation of solid adenocarcinomas in syngeneic recipients. Ad.RSV-tk injection of the tumor followed by intraperitoneal ganciclovir application caused highly significant tumor volume reduction and necrosis. These results indicate that transduction of the HSV-tk gene followed by ganciclovir is highly efficient for growth inhibition of hepatic metastases of pancreatic carcinoma.
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PMID:Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors. 921 89

Adenovirus (Ad) gene transfer vectors traffic to regional lymph nodes (RLNs) after footpad injections in mice, resulting in localized production of interferon gamma (IFN-gamma). With this background, we evaluated the hypothesis that Ad vector administration may inhibit RLN tumor metastasis independent of the transgene in the expression cassette. Tumors of MM48, a cell line with a propensity toward lymphogenous metastasis, were established in the footpads of syngeneic C3H mice, and E1(-)E3(-) Ad vectors encoding no transgene (AdNull) or encoding an irrelevant transgene (AdCD; Escherichia coli cytosine deaminase with no 5-fluorocytosine administration) were administered (10(10) particles) in a peritumoral location. Both vectors suppressed the growth of tumor in the regional (popliteal) lymph node. This effect was localized to the regional, but not distant, lymph nodes (p < 0.05). Heat inactivation of the vector or decreasing the dose of the vector to 10(9) particles did not suppress RLN growth of the tumor when compared with 10(10) particles of active AdNull (p < 0.05 and p < 0.01, respectively). The ability of an E1(-)E4(-) vector expressing beta-galactosidase (AdRSVbetagal.11) to suppress RLN tumor growth showed that the E4 region of the Ad vector was not responsible for the effect. Blocking either IFN-gamma or natural killer (NK) cells with systemic antibody treatment in immunocompetent mice allowed rapid growth of RLN metastases despite Ad vector administration, and Ad vector injection into the footpads of tumor-free mice induced the accumulation of NK cells in the RLN. These data demonstrate that, in a metastatic murine tumor model, a low dose (10(10) particles) of replication-deficient Ad vectors inhibits RLN metastases independent of a therapeutic transgene, an effect that is mediated, at least in part, by IFN-gamma and NK cells.
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PMID:Adenovirus gene transfer vectors inhibit growth of lymphatic tumor metastases independent of a therapeutic transgene. 1153 67

Adenovirus-mediated gene therapy is hampered by severe virus-related toxicity, especially to the liver. The aim of the present study was to test the ability of a vascular exclusion technique to achieve transgene expression within selected liver segments, thus minimizing both viral and transgene product toxicity to the liver. An E1-E3-deleted replication-deficient adenovirus expressing a green fluorescent protein (GFP) reporter gene was injected into the portal vein of BDIX rats, with simultaneous clamping of the portal vein tributaries to liver segments II, III, IV, V, and VIII. GFP expression and inflammatory infiltrate were measured in the different segments of the liver and compared with those of the livers of animals receiving the viral vector in the portal vein without clamping. The GFP expression was significantly higher in the selectively perfused segments of the liver as compared with the non-perfused segments (p < 0.0001) and with the livers of animals that received the vector in the portal vein without clamping (p < 0.0001). Accordingly, the inflammatory infiltrate was more intense in the selectively perfused liver segments as compared with all other groups (p < 0.0001). Fluorescence was absent in lungs and kidneys and minimal in spleen. The clinical usefulness of adenovirus-mediated gene transfer to the liver largely depends on the reduction of its liver toxicity. Clamping of selected portal vein branches during injection allows for delivery of genes of interest to targeted liver segments. Transgene expression confined to selected liver segments may be useful in the treatment of focal liver diseases, including metastases.
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PMID:Adenovirus-mediated gene transfer into selected liver segments using a vascular exclusion technique. 1180 95

Adenovirus-based gene therapy may provide an alternative mode of treatment for prostate cancer, especially for late-stage and androgen-independent disease for which there is currently no effective treatment. Efficient adenovirus infection of target cells depends upon the presence of the coxsackie adenovirus cell surface receptor, CAR, which is the primary receptor for group C adenoviruses and is important for the attachment of adenovirus to the cell membrane. To evaluate the potential efficacy of adenoviral therapy for prostate cancer, we evaluated CAR expression in normal prostate tissue and in prostate carcinoma of increasing Gleason grades in paraffin-embedded, archival tissues using a polyclonal antibody raised against human CAR. Immunohistochemical analysis of benign prostate epithelia demonstrated intense luminal and lateral cell membrane staining. There was a statistically significant difference in CAR membrane expression with respect to Gleason score. In addition, metastatic prostate specimens demonstrated strong membrane staining for CAR. Adenovirus therapy may, therefore, provide an alternate modality in the treatment of prostate cancer and may be especially efficacious in the treatment of metastatic disease.
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PMID:Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy. 1209 94

Tamoxifen has contributed to a dramatic reduction in breast cancer mortality and recent results indicate that aromatase inhibitors may further improve survival in some patients. Nevertheless, a substantial proportion of patients become resistant to treatment. To date, with the exception of estrogen receptor (ER) determination by ligand binding or immunohistochemical techniques, there has been no way of predicting which of several therapies is indicated in particular patients. We describe a novel assay using the adenoviral gene delivery system to assess ER function in breast cancer cells derived directly from patients. The purification and short-term culture of these cells has been recently described by our laboratory. Adenovirus containing an estrogen-regulated beta-galactosidase reporter gene (ERE-lacZ) was constructed and used to test ER activity in breast cancer cells derived from 18 patients with primary and 16 patients with metastatic cancer, under varying treatment schedules. The adenoviral assay enabled ER activity to be readily determined in purified cells from primary breast cancers and secondary sites. Breast cancers cells could be categorized on the basis of ER activity in the absence of ligand, the presence of estrogen or anti-estrogens. In primary breast cancers, our results correlated with ER determination by immunohistochemistry in 78% of cases. In patients who had become resistant to tamoxifen, however, we found some in whom reporter activity was stimulated by tamoxifen and others whose tumors were either still estrogen responsive or completely unresponsive, irrespective of the original ER content. Our findings indicate that this reporter assay could be useful in decisions regarding use of adjuvant endocrine therapies in breast cancer.
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PMID:Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: a pilot study. 1456 18

The improvement of initial tumor cell transduction with viral vectors is a major task in tumor gene therapy. We have developed mouse tumor models with hepatic metastases to study transduction of tumor cells after systemic adenovirus vector application. The tumor models were established by intraportal transplantation of human tumor cell lines into immunodeficient mice. Liver metastases derived from cervix, colon, breast, and liver cancer lines were analyzed for distribution of extracellular matrix, vascularization, and transgene expression after tail vein injection of adenovirus vectors. Overall, xenografts resembled the morphology of corresponding tumors in cancer patients. Adenovirus-mediated gene delivery depended on tumor vascularization and direct contact between blood vessels and tumor cells. These models represent important tools for studying and improving tumor gene therapy approaches.
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PMID:Xenograft models for liver metastasis: Relationship between tumor morphology and adenovirus vector transduction. 1512 Mar 25

Adenovirus vectors have a number of advantages for gene therapy. However, because of their lack of tumor tropism and their preference for liver infection following systemic administration, they cannot be used for systemic attack on metastatic disease. Many epithelial tumors (e.g., colon, lung, and breast) express carcinoembryonic antigen (CEA). To block the natural hepatic tropism of adenovirus and to "retarget" the virus to CEA-expressing tumors, we used a bispecific adapter protein (sCAR-MFE), which fuses the ectodomain of the coxsackie/adenovirus receptor (sCAR) with a single-chain anti-CEA antibody (MFE-23). sCAR-MFE untargets adenovirus-directed luciferase transgene expression in the liver by >90% following systemic vector administration. Moreover, sCAR-MFE can "retarget" adenovirus to CEA-positive epithelial tumor cells in cell culture, in s.c. tumor grafts, and in hepatic tumor grafts. The sCAR-MFE bispecific adapter should, therefore, be a powerful agent to retarget adenovirus vectors to epithelial tumor metastases.
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PMID:Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter. 1754 16

Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-x(L). Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-x(L) renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2- or Bcl-x(L)-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-x(L) cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease.
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PMID:Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. 1754 25

Adenovirus vectors (Ad) have been frequently used for cancer gene therapy research because of their high gene transduction efficiency. However, systemic administration of conventional Ad can lead to the acute accumulation of virus particles and transgene expression in the liver, which may cause severe hepatotoxicity. For these reasons, clinical application of Ad for systemic administration has been limited, although intratumor administration of Ad has shown marked antitumor effects. Therefore, to promote the application of Ad in systemic cancer gene therapy, especially against the distant metastatic cancer, a novel Ad with marked accumulation in tumors and minimal hepatic distribution is needed. From this perspective, bioconjugation with polyethylene glycol (PEGylation) to Ad surface is a promising strategy, and we are trying to develop cancer targeted Ad by PEGylation approach. Through our study, we particularly clarified that PEGylated Ad (PEG-Ad) with optimized PEG modification ratio exhibited the enhanced distribution and gene expression in tumor tissue via systemic injection, which was based on the enhanced permeability and retention (EPR) effect. Moreover, PEG-Ad encoding therapeutic gene demonstrated not only stronger tumor-suppressive activity but also fewer hepatotoxic side effects compared with conventional Ad. In addition, we further attempted the active targeting using targeting ligand on the tip of PEG. We revealed that PEG-Ad with transferrin as a tumor targeting ligand could transduce more efficiently into tumor cells, which express transferrin receptor, compared with conventional PEG-Ad. In this symposium, I will present our approach for development of cancer targeted Ad by PEGylation.
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PMID:[Development of pegylated adenovirus vector for cancer gene therapy]. 1904 92


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