Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Mediterranean diet, rich in fresh fruits and vegetables, has been associated with a lower incidence of cardiovascular disease and cancer, partly because of its high proportion of bioactive compounds such as vitamins, flavonoids and polyphenols. The major lipid component of such diet is the drupe-derived olive oil, that can be distinguished from other seed oils for the peculiar composition of its non-triglyceride fraction. In fact, several minor components, including polyphenols, grant the oil its particular taste and aroma. Oleuropein, the most abundant among these components, has been shown to be a potent antioxidant endowed with antiinflammatory properties. We investigated the effects of oleuropein on NO release in cell culture and its activity toward nitric oxide synthase (iNOS) expression. The results show that oleuropein dose-dependently enhance nitrite production in LPS-challenged mouse macrophages. This effect was blocked by the iNOS inhibitor L-NAME, indicating increased iNOS activity. Also, Western blot analysis of cell homogenates show that oleuropein increases iNOS expression in such cells. Taken together, our data suggest that, during endotoxin challenge, oleuropein potentiates the macrophage-mediated response, resulting in higher NO production, currently believed to be beneficial for cellular and organismal protection.
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PMID:Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages. 946 66

meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [131I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by 86Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [51Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca2+-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 microM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application.
Cancer Chemother Pharmacol 1998
PMID:Renal toxicity of the neuron-blocking and mitochondriotropic agent m-iodobenzylguanidine. 961 56

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

There is great interest in the development of gene therapeutic strategies for the treatment of benign and malignant diseases. Recombinant adenovirus has a wide spectrum of tissue specificity and is an efficient vector delivery system. Successful gene delivery, however, requires viral entry into the target cells via specific receptor-mediated uptake. Recently, a cDNA clone (the coxsackie and adenovirus receptor [CAR]) encoding a 46-kDa protein was identified as the receptor for group C adenovirus (e.g., adenovirus type 2 and 5). Currently, little is known regarding the expression of adenoviral receptor in normal tissue and cancer. In this paper, we have documented a significant difference in viral receptor levels that may be due to transcriptional regulation of the CAR gene in several human bladder cancer cell lines. The differences in viral receptor levels in these cells correlated with their sensitivity to viral infection. Transfection of receptor-negative cell line with CAR cDNA led to increased virus binding and increased susceptibility to adenovirus-mediated gene delivery. Our results demonstrate that the expression of adenoviral receptor is variable among human bladder cancer cells. This variability may have a significant impact on the outcome of adenovirus-based gene therapy.
Cancer Res 1999 Jan 15
PMID:Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. 992 41

We investigated a series of clinically well documented pancreatic ductal adenocarcinomas for the presence of molecular alterations of the p53 and Ki-ras genes and their correlations with p53 nuclear immunohistochemical expression. The results were evaluated in comparison with cellular expression, by ductal cancer cells, of gastric (PGII) and intestinal (CAR-5) antigens and with several clinicopathologic parameters such as grade, stage, size and lymph-node status. Ki-ras gene mutation at codon 12 was detected in 77.7% of cases with no relationship with tumor grade, stage, and survival of the patients. p53 gene mutations were found in 18/31 (58%) cases and p53 immunohistochemical overexpression was detected in 51/104 (49%) of cases. Both Ki-ras and p53 gene mutations were found in 13/31 (41.9%) of adenocarcinomas examined, while Ki-ras and p53 overexpression was detected in 19/45 (42.2%). A positive correlation between p53 overexpression and tumour grade was found (p0.0001) but no relationship was found between p53 overexpression, tumor stage, lymph-node status and size of the tumors. A trend toward an association of p53 overexpression with poorer survival was found in patients with pancreatic cancers of the same grade, stage or with the same immunophenotype, but the data did not reach statistical significance. The expression of gastric and intestinal antigenic markers in pancreatic adenocarcinomas and the presence of molecular abnormalities analogous to those found in gastric and colorectal cancers suggest common genetic pathways in gastrointestinal and pancreatic carcinogenesis.
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PMID:Ki-ras and p53 gene mutations in pancreatic ductal carcinoma: a relationship with tumor phenotype and survival. 1007 72

The utility of adenoviral vectors for cancer therapy is limited due to their lack of specificity for tumor cells. In order to target adenovirus to tumor, the natural tropism of the adenovirus should be ablated and replaced by a tumor-specific binding domain. To this end, a neutralizing anti-fiber antibody conjugated to an anti-EpCAM antibody was created that targets the adenovirus to the EpCAM antigen present on tumor cells. The EpCAM antigen was chosen as the target because this antigen is highly expressed on a variety of adenocarcinomas of different origin such as breast, ovary, colon and lung, whereas EpCAM expression is limited in normal tissues. In these studies, the EpCAM-targeted adenovirus was shown to infect specifically cancer cell lines of different origin expressing EpCAM such as ovary, colon and head and neck. Gene transfer was blocked by excess anti-EpCAM antibody and dramatically reduced in EpCAM negative cell lines, thus showing the specificity of the EpCAM-targeted adenovirus. Importantly, infection with targeted adenovirus was independent of CAR, which is the natural receptor for adenovirus binding, since blocking of CAR with recombinant fiber knob did not affect infection with targeted adenovirus. Apart from the cancer cell lines, the efficacy of targeted viral infection was studied in freshly isolated primary human colon cancer cells. As colon cancer predominantly metastasizes to liver, and adenovirus has a high tropism for hepatocytes, we also sought to determine if the EpCAM-targeted adenovirus showed reduced infectivity of human liver cells. The bispecific antibody could successfully mediate gene transfer to primary human colon cancer cells, whereas it almost completely abolished infection of liver cells. This work thus demonstrates that EpCAM-targeted adenoviral vectors can be specifically directed to a wide variety of adenocarcinomas. This approach may prove to be useful for selective gene therapy of cancer.
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PMID:Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM. 1046 71

Induction of haem oxygenase-1 (HO-1) as well as nitric oxide (NO) biosynthesis during tumour growth was investigated in an experimental solid tumour model (AH136B hepatoma) in rats. An immunohistochemical study showed that the inducible isoform of NO synthase (iNOS) was localized in monocyte-derived macrophages, which infiltrated interstitial spaces of solid tumour, but not in the tumour cells. Excessive production of NO in the tumour tissue was unequivocally verified by electron spin resonance spectroscopy. Tumour growth was moderately suppressed by treatment with either Nomega-nitro-L-arginine methyl ester (L-NAME) or S-methylisothiourea sulphate (SMT). In contrast, HO-1 was found only in tumour cells, not in macrophages, by in situ hybridization for HO-1 mRNA. HO-1 expression in AH136B cells in culture was strongly enhanced by an NO (NO+) donor S-nitroso-N-acetyl penicillamine. HO-1 mRNA expression in the solid tumour in vivo decreased significantly after treatment with low doses of NOS inhibitors such as L-NAME and SMT (6-20 mg kg(-1)). However, the level of HO-1 mRNA in the solid tumour treated with higher doses of NOS inhibitor was similar to that of the solid tumour without NOS inhibitor treatment. Strong induction of HO-1 was also observed in solid tumours after occlusion or embolization of the tumour-feeding artery, indicating that ischaemic stress which may involve oxidative stress triggers HO-1 induction in the solid tumour. Lastly, it is of great importance that an HO inhibitor, zinc protoporphyrin IX injected intra-arterially to the solid tumour suppressed the tumour growth to a great extent. In conclusion, HO-1 expression in the solid tumour may confer resistance of tumour cells to hypoxic stress as well as to NO-mediated cytotoxicity.
Br J Cancer 1999 Aug
PMID:Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. 1047 Oct 43

The addition of replication-defective recombinant adenovirus to plasmid transfection (termed here "adenofection") has been shown to increase plasmid transgene expression in limited studies. Similarly, the addition of cationic liposomes to adenovirus increases adenovirus-mediated gene transduction (termed here "lipoduction"). Here we demonstrate that adenofection was effective at enhancing transgene expression when used in conjunction with a variety of different transfection reagents, including a monocationic liposome, a polycationic liposome, an activated dendrimer, a large multilamellar liposomal vesicle, and a protein/amphipathic polyamine complex. The effect was seen regardless of the cellular expression of the adenovirus receptor, CAR, in three different human cancer cell lines derived from rhabdomyosarcomas (Rh18 and RD, CAR-) and cervical carcinoma (HeLa, CAR+). The protein/amphipathic polyamine complex showed an adenofection effect but did not show a lipoduction effect, consistent with different mechanisms of action for adenofection and lipoduction. Using dual-color flow cytometric analysis of cells transfected with a plasmid expressing the enhanced blue fluorescent protein (pEBFP) and a recombinant adenovirus expressing the green fluorescent protein (Ad5-GFP), we demonstrate that adenofection works primarily by increasing gene expression within a cell, whereas lipoduction increases the percentage of cells expressing the transgene. In addition, these studies show that both adenofection and lipoduction can occur simultaneously, further increasing gene transfer. The combination of lipofection and adenovirus transduction also prolonged the duration of transient gene expression and was generally no more toxic than lipofection alone. The enhancement of gene transfer was also seen after injection of complexes directly into subcutaneous human xenograft tumors. Therefore, more effective gene transfer in vitro and in vivo of either plasmid DNA, adenovirus DNA, or both can be achieved by combining liposomal transfection with adenoviral transduction.
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PMID:Reciprocal enhancement of gene transfer by combinatorial adenovirus transduction and plasmid DNA transfection in vitro and in vivo. 1051 60

In our recent study we described a significant antileukemic efficacy of a combination therapy with interleukin-12 (IL-12) and doxorubicin (DOX) in the L1210 leukemia model. This therapeutic effect was abrogated by elimination of activated macrophages. Activated macrophages produce a variety of factors that can contribute to the elimination of tumor cells in vivo, including proteases, TNF, reactive oxygen intermediates, and nitric oxide (NO). Based on the results of previous reports, the contribution of NO in potentiated antileukemic effects of IL-12 + DOX combination seemed to be highly possible. Both DOX and IL-12 given alone increased the production of NO by peritoneal macrophages, however, macrophages derived from the mice treated with the combination of those agents produced significantly less NO than macrophages from IL-12-alone-treated mice. Production of NO by spleen macrophages after IL-12 + DOX treatment was higher than it was in controls, IL-12-alone or DOX-alone-treated groups. In serum, concentrations of NOx- in IL-12- or IL-12 + DOX-treated mice were significantly higher in comparison with controls, however not significantly different from each other. Addition of L-NAME treatment to the IL-12 + DOX therapy in leukemia-bearing mice did not significantly change the antileukemic efficacy of this therapy. Thus, our results indicate that the augmented antileukemic effects of IL-12 + DOX combination therapy in L1210 model are NO-independent. Therefore, further studies on the possible mechanisms of potentiated antileukemic activity of combination of IL-12 and DOX would be worth pursuing.
Cancer Lett 1999 Dec 01
PMID:The potentiated antileukemic effects of doxorubicin and interleukin-12 combination are not dependent on nitric oxide production. 1066 91

The utility of current generation adenoviral vectors for targeted, cell-specific gene delivery is limited by the promiscuous tropism of the parent virus. To address this issue, we have developed both genetic and immunologic methods to alter viral tropism. Immunologic retargeting has been achieved via conjugates comprised of an antifiber knob Fab and a targeting moiety consisting of a ligand or antireceptor antibody. Gene delivery by this approach has been accomplished via a variety of cellular pathways including receptors for folate, FGF, and EGF. In addition to cell-specific gene delivery, this strategy has allowed enhanced gene delivery to target cells lacking the native adenoviral receptor, CAR. Of note, this specific and extended gene delivery allowed enhanced survival in murine models of human carcinoma via cancer gene therapy. Genetic strategies to alter adenoviral tropism have included both fiber modification and fiber replacement. In the former, we have identified the HI loop of fiber as a propitious locale for introduction of heterologous peptides. Incorporation of an RGDC peptide at this locale allowed gene delivery via cellular integrins with dramatic efficiency augmentations. As a strategy to achieve both new tropism as well as to ablate native tropism, methods have been developed to replace the fiber protein with heterologous motif which preserves the key trimeric quaternary structure of fiber and allows for propagation. Such a fiber-replacement virus has been rescued and has demonstrated capacities consistent with its utility as a novel vector agent. These strategies have allowed the achievement of cell-specific gene delivery via adenoviral vectors and thus have the potential to enhance the utility of this vector agent.
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PMID:Strategies to adapt adenoviral vectors for targeted delivery. 1066 12


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