Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the antiangiogenic agent TNP-470 does not, in general, increase the cytotoxicity of anti-cancer therapies in cell culture, the antiangiogenic agents TNP-470 and minocycline individually and especially in combination have been shown to increase the tumor growth delay produced by several standard cytotoxic therapies in the Lewis lung carcinoma. In an effort to understand the mechanism by which the antiangiogenic agent combination TNP-470/minocycline potentiates the antitumor activity of cytotoxic therapeutic agents in vivo, the biodistribution of [14C]-cyclophosphamide and cis-diamminedichloroplatinum(II) was determined 6 h after cytotoxic drug administration in animals bearing Lewis lung carcinoma pretreated with TNP-470/minocycline and in animals without pretreatment. Higher levels of 14C and platinum were found in 9 tissues (including tumor) except blood in animals pretreated with TNP-470/minocycline. The increased drug levels in the tumors may be sufficient to account for the increased tumor growth delays observed previously. DNA alkaline elution of tumors from animals pretreated with TNP-470/minocycline showed increased DNA cross-linking by both cyclophosphamide and cis-diamminedichloroplatinum(II). The possible implications of these results are discussed.
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PMID:Antiangiogenic treatment (TNP-470/minocycline) increases tissue levels of anticancer drugs in mice bearing Lewis lung carcinoma. 853 29

Antiangiogenic therapy may represent a promising approach to cancer treatment. Indeed, the efficacy of endogenous angiogenesis inhibitors, including angiostatin, endostatin and TIMPs, has been demonstrated in many types of solid tumors in animal models. In view of the possible problems associated with long-term administration of inhibitors as recombinant proteins, we propose their delivery as nucleic acids through a gene therapy approach. To this end, eukaryotic expression constructs for murine angiostatin and endostatin as well as human TIMP-2 were generated, and characterized in vitro. All constructs carry the relevant cDNAs under the control of the strong HCMV promoter/enhancer, and cleavable leader signals to allow protein secretion. Expression of the angiogenesis inhibitors was detected by in vitro transcription/translation experiments as well as transfection of 293T cells, followed by Western blotting (WB) or radioimmunoprecipitation analysis of both cell lysates and supernatants (SNs). These constructs might be used for in vivo intramuscular delivery of plasmid DNA and as a set of reagents for the development of retroviral as well as adeno-associated viral (AAV) vectors expressing angiogenesis inhibitors.
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PMID:Generation of expression plasmids for angiostatin, endostatin and TIMP-2 for cancer gene therapy. 1066 55

Endostatin is a C-terminal fragment of collagen XVIII and has potent anti-angiogenic and anti-tumor activity. Mouse endostatin-coding sequences were obtained using PCR and linked to the signal sequence of influenzavirus hemagglutinin. The signal-sequence endostatin fragment was subcloned into plasmid vectors under the transcriptional control of cytomegalovirus promoter. Murine renal carcinoma (Renca) cells transfected with endostatin-coding plasmid are shown to secrete full-length endostatin. Endostatin-secreting Renca cells demonstrate slower growth in vivo compared to empty vector-transfected cells, but their in vitro growth is unaffected. Anti-angiogenic activity of secreted endostatin was confirmed in a Matrigel angiogenesis assay in vivo. We report growth inhibition of Renca tumors resulting from intra-tumoral delivery of plasmid vector encoding secretable endostatin. Elevated local concentrations of endostatin resulted from multiple intra-tumoral injections of endotoxin-purified plasmid DNA. Local endostatin levels were high enough to obtain growth arrest of Renca tumors.
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PMID:Intra-tumoral administration of naked plasmid DNA encoding mouse endostatin inhibits renal carcinoma growth. 1127 88

Although electroporation has been shown in recent years to be a powerful method for delivering genes to muscle, no gene therapy via electro-injection has been studied for the treatment of tumors. In an immunocompetent tumor-bearing murine model, we have found that delivery of a low dose of reporter gene DNA (10 microg) to muscle via electroporation under specific pulse conditions (two 25-ms pulses of 375 V/cm) increased the level of gene expression by two logs of magnitude. Moreover, administration of 10 microg of interferon (IFN)-alpha DNA plasmid using these parameters once a week for 3 weeks increased the survival time and reduced squamous cell carcinoma (SCC) growth at a distant site in the C3H/HeJ-immunocompetent mouse. IFN-alpha gene therapy delivered to muscle using electroporation demonstrated statistically significant (P < 0.05) therapeutic efficacy for treating SCC located at a distant site, compared with interleukin (IL)-2 or endostatin gene, also delivered by electro-injection. The increased therapeutic efficacy was associated with a high level and extended duration of IFN-alpha expression in muscle and serum. We also discovered that the high level of IFN-alpha expression correlated with increased expression levels of the antiangiogenic genes IP-10 and Mig in local tumor tissue, which may have led to the reduction of blood vessels observed at the local tumor site. Delivery of increasing doses (10-100 microg) of IFN-alpha plasmid DNA by injection alone did not increase antitumor activity, whereas electroporation delivery of increasing doses (10-40 microg) of IFN-alpha plasmid DNA did increase the survival time. Our data clearly demonstrate the potential utility of electroporation for delivery of gene therapy to muscle for the treatment of residual or disseminated tumors.
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PMID:Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site. 1131 17

Antiangiogenesis strategy has been widely recognized as a viable approach to fight cancer. Considering the high cost and inconvenience of protein therapy of endostatin (ES), which is a potent antiangiogenic protein, we attempted to explore the inhibitory effect of ES gene therapy on tumor growth and metastasis. In this experiment, Lewis lung carcinoma (LLC)-bearing C57/BL mice were used to evaluate the antitumor effect of ES gene therapy and its impairment of tumor neovasculature. The data showed that the ectopic ES in circulation expressed by intramuscular administration of formulated ES-encoding plasmid DNA significantly suppressed primary tumor growth and lung metastasis in LLC-bearing C57/BL mice. Hence, our results demonstrated the inhibitory effect of ES gene therapy on angiogenesis-dependent tumor growth and metastasis.
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PMID:Anticancer treatment of endostatin gene therapy by targeting tumor neovasculature in C57/BL mice. 1132 48

Tumor growth and metastasis are angiogenesis-dependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. We previously reported that it is possible to inhibit primary tumor growth and metastasis in a transgenic model of spontaneous breast tumor, which shows many similarities to its human counterpart (including ability to metastasize) by intratumoral administration of a DNA construct carrying the murine angiostatin cDNA driven by liposomes. Here we report that it is also possible to achieve this goal by a systemic (intraperitoneal) delivery of therapeutic DNA constructs carrying genes coding for mouse and human anti-angiogenic factors which include angiostatin, endostatin and TIMP-2. These findings may be relevant to the design of therapeutic interventions in humans.
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PMID:Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice. 1140 3

We have performed association studies between a novel coding single nucleotide polymorphism (D104N) in endostatin, one of the most potent inhibitors of angiogenesis, and prostate cancer. We observed that heterozygous N104 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous D104 subjects (odds ratio, 2.4; 95% confidence interval, 1.4-4.16). Modeling of the endostatin mutant showed that the N104 protein is stable. These results together with the observation that residue 104 is evolutionary conserved lead us to propose that: (a) the DNA segment containing this residue might contain a novel interaction site to a yet unknown receptor; and (b) the presence of N104 impairs the function of endostatin.
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PMID:A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma. 1160 64

To isolate matrix molecules with angiogenic activity, tumor extracellular matrix (ECM) fractions from the basement membrane preparation Matrigel were analyzed for effects on endothelial cell (EC) proliferation, differentiation, and vessel formation in vivo. Inhibition of human and bovine EC DNA synthesis was evident upon treatment with several soluble Matrigel fractions including conditioned media (MGCM). After size fractionation of MGCM, EC growth arrest was activated by factor(s) smaller than 3,000 daltons (3KF). Bovine EC differentiation (tube formation) was promoted by both MGCM and 3KF fractions in two different models using matrigel or collagen gels to stimulate tube formation. The 3KF factor(s) stimulated angiogenesis when implanted in the cornea or subcutaneously in mice. FGF-induced angiogenesis and blood flow were increased in the presence of 3KF factor(s), an effect that was inhibited by the anti-angiogenic molecule endostatin. Further characterization of the low molecular weight 3KF samples by RP-HPLC revealed several fractions exhibiting EC growth arrest activity. These results suggest that the ability of ECM preparations to induce EC growth arrest and tube formation may reside, at least partially, in previously undetected low molecular weight molecules. Characterization of these ECM-associated inhibitors may lead to the development of novel anti-angiogenic and anti-tumor compounds.
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PMID:Extracellular matrix-derived angiogenic factor(s) inhibit endothelial cell proliferation, enhance differentiation, and stimulate angiogenesis in vivo. 1182 74

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

Human endostatin cDNA was cloned from total RNA of normal Chinese liver cell line L02 by RT-PCR. Endostatin DNA sequence encoded 184 amino acid residues. Five base pairs and 3 amino acid residues are different from that reported, it may be due to interspecies difference. The endostatin cDNA was inserted into the pET-28a(+) containing T7 promoter. The recombinant plasmid was transformed the E.coli BL21(DE3). Recombinant human endostatin was highly expressed as inclusion body when the expression strain BL-ENDO was induced with 1 mmol/L IPTG. Result of SDS-PAGE analysis revealed that recombinant human endostatin was accounted for up to 25% of soluble protein in E.coli. Purified and refolded recombinant human endostatin was active in inhibiting tumor growth and metastasis.
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PMID:Cloning, Expression and Tumor Suppression of Human Endostatin. 1207 17


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