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)

The high resistance of bacterial spores to heat has been repeatedly postulated to be due to stabilization of spore biopolymers by metal chelate compounds. Binding of calcium dipicolinic acid (Ca(II)-DPA) with spore proteins and amino acids has been discussed in the literature, but equilibrium data are generally lacking. By means of potentiometric pH titrations at 25 degrees C and an ionic strength of 1.0 (KNO(3)), the formation of Ca(II)-DPA (1:1 and 1:2) chelates and the interactions of Ca(II)-DPA chelate with a mole of each of three typical amino acids viz., cysteine, alanine, and glycine has been investigated. Analysis of the potentiometric data indicates that calcium and DPA forms 1:1 and 1:2 chelates with log K(ML1) = 4.39 +/- 0.01 and log K(ML2) = 2.25 +/- 0.01. In the presence of an equimolar amount of each of the amino acids under consideration, the Ca(II)-DPA chelate forms mixed ligand (ternary) chelate yielding the following stepwise stability constants: log K(1) = 4.17 +/- 0.01, log K(2) = 0.78 +/- 0.01 for cysteine, log K(1) = 4.06 +/- 0.01, log K(2) = 0.65 +/- 0.01 for alanine, and log K(1) = 4.30 +/- 0.02, log K(2) = 0.11 +/- 0.01 for glycine. Methods for calculating the stability constants of the mixed ligand system have been developed. On the basis of the potentiometric equilibrium data, possible structures for the various calcium chelate species are discussed. The data suggest that the differences in heat resistance of various strains of bacterial spores may conceivably be related to the differences in composition and stability of coordination complexes in the spore.
Biophys J 1968 Dec
PMID:Mixed chelates of Ca(II)-pyridine-2,6-dicarboxylate with some amino acids related to bacterial spores. 571 54

1. Nitric oxide (NO), an inhibitory neurotransmitter released from peripheral neurones, hyperpolarizes smooth muscle cells and inhibits contraction. The mechanism of this hyperpolarization is unknown. 2. We have identified three classes of K+ channels activated by NO and NO donors in colonic smooth muscle cells. NO and NO donors increased the open probability of 80 pS channels (KNO1), very small channels (< 4 pS, KNO2), and 270 pS Ca(2+)-activated K+ channels (BK channels) in cell-attached patches. 3. Dibutyryl cGMP and 8-bromo cGMP also increased the open probability of KNO1 and KNO2 in cell-attached patches. 4. In excised patches of membrane, direct application of NO or the NO donor, S-nitroso-N-acetyl penicillamine (SNAP), increased the open probability of KNO1 and KNO2, but cGMP or dibutyryl cGMP had no effect. SNAP had no effect on the open probability of BK channels in excised patches. 5. The reducing agent dithiothreitol and the alkylating agent N-ethylmaleimide blocked NO-induced channel openings. 6. In summary, the hyperpolarization response to NO in smooth muscles may be mediated by multiple K+ channels. At least two of these classes of channels may be activated by dual pathways involving direct activation by NO and cGMP-mediated mechanisms.
J Physiol 1995 Dec 15
PMID:Nitric oxide activates multiple potassium channels in canine colonic smooth muscle. 878 38

Nineteen types, the product of 33 genes, comprise the collagen family of proteins. Types I, II, III, V, and XI constitute the fibrillar collagens, whereas types IV, VI to X, and XII to XIX represent the structurally diverse, nonfibrillar members. Type XIX collagen was discovered from the sequence of rhabdomyosarcoma cDNA clones. The type XIX chain consists of 1142 amino acids that contribute primarily to a unique five subdomain triple-helical region. To characterize the protein, to determine the tissue distribution, and to provide some insight into its function, we generated two type XIX-specific polyclonal antibodies. One was directed against a recombinant molecule containing amino-terminal sequences, and the second was derived from a synthetic peptide corresponding to most of the short carboxy terminus. These antibodies were used in immunoblot assays of rhabdomyosarcoma cell/matrix homogenates to identify a 165-kd disulfide-bonded and bacterial collagenase-sensitive protein. Immunohistochemical analysis of type XIX collagen was performed for human skeletal muscle, spleen, prostate, kidney, liver, placenta, colon, and skin. In contrast to Northern blot hybridizations, which showed very low levels of the 12-kb transcript in few tissues, the protein was found in all tissues examined. The type XIX collagen distribution was restricted to vascular, neuronal, mesenchymal, and some epithelial basement membrane zones, which is similar to the profile recently established (Ref. 8) and further extended here for type XV collagen. Nevertheless, localization of type XIX exhibited significant differences from type XV collagen that were particularly evident in the kidney, liver, and spleen. This report, in conjunction with the type XV results and other studies of type XVIII collagen, indicates the existence of a new collagen subgroup founded on their widespread presence in basement membrane zones regardless of chain homology. In addition to their role in basement membrane-stromal interactions, the pronounced vascular association suggests involvement of these related collagen types with angiogenic and pathological processes.
Am J Pathol 1997 Dec
PMID:Biochemical and immunohistochemical characterization of human type XIX defines a novel class of basement membrane zone collagens. 940 23

Recently, fragments of extracellular proteins, including endostatin, were defined as a novel group of angiogenesis inhibitors. In this study, human plasma equivalent hemofiltrate was used as a source for the purification of high molecular weight peptides (10-20 kDa), and the isolation and identification of circulating human endostatin are described. The purification of this C-terminal fragment of collagen alpha1(XVIII) was guided by MALDI-MS and the exact molecular mass determined by ESI-MS was found to be 18 494 Da. N-terminal sequencing revealed the identity of this putative angiogenesis inhibitor and its close relation to mouse endostatin. The cysteine residues 1-3 and 2-4 in the molecule are linked by disulfide bridges. In vitro biological characterization of the native protein demonstrated no anti-proliferative activity on different endothelial cell types. These data indicate that human endostatin, which is a putative angiogenesis inhibitor, is present in the circulation.
FEBS Lett 1997 Dec 29
PMID:Isolation and characterization of the circulating form of human endostatin. 945 95

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.
Clin Cancer Res 1997 Dec
PMID:Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer. 981 33

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
Cancer Res 1998 Dec 15
PMID:Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy. 986 20

Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m2) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration-time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC0-t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC0-infinity, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 micrograms * hr/ml; p = 0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
J Pharmacokinet Biopharm 1998 Dec
PMID:Pharmacokinetics and relative bioavailability of carboxyamido-triazole with respect to food and time of administration: use of a single model for simultaneous determination of changing parameters. 1048 80

Endostatin, a potent inhibitor of angiogenesis and tumor growth, is a COOH-terminal fragment of collagen XVIII derived through cleavage of an Ala-His linkage by an as yet unidentified endostatin-processing enzyme. Endostatin was originally isolated from the conditioned medium of hemangioendothelioma (EOMA) cells. By investigating the processing of collagen XVIII to endostatin by EOMA cells, we show here that the generation of endostatin can be mediated by an elastase activity. We also show that several members of the elastase family can act as an endostatin-processing enzyme by specifically cleaving the Ala-His linkage and releasing endostatin from a precursor molecule. We further suggest that the generation of endostatin from collagen XVIII is at least a two-step process, involving a metal-dependent early step and an elastase activity-dependent final step.
Cancer Res 1999 Dec 15
PMID:The generation of endostatin is mediated by elastase. 1062 89

Angiogenesis is required for tumor formation. Several studies have demonstrated that tumor angiogenesis is regulated by a balance between proangiogenesis and antiangiogenesis factors and that this balance varies in different organ environments. To investigate whether expression of an angiogenesis inhibitor by cancer cells could alter this balance and prevent tumor formation in different organ environments, we engineered stable transfectants from RenCa mouse renal carcinoma cells and SW620 human colon carcinoma cells to constitutively secrete a mouse endostatin protein with c-myc and polyhistidine (His) tags. Production and secretion of the endostatin-c-myc-His fusion protein by endostatin-transfected cells were confirmed by immunofluorescence staining and Western blot analysis. The endostatin transfectants and control transfectants, stably transfected with a control plasmid, had similar in vitro growth rates compared with their parental cell lines. Conditioned medium from endostatin-transfected cells inhibited human umbilical vein endothelial cell proliferation by 36-51% compared with conditioned medium from control cells. After inoculation into mice, flank tumors from endostatin-transfected cells were 73-91% smaller than flank tumors from control cells after 3 weeks. Inoculation of a cell mixture containing 25% endostatin-transfected cells and 75% control cells resulted in inhibition of flank tumor formation as effective as after inoculation of 100% endostatin-transfected cells. Formation of lung metastases by RenCa endostatin-transfected cells and formation of liver metastases by SW620 endostatin-transfected cells were dramatically inhibited compared with formation of metastases by control cells. These findings demonstrate that endostatin can inhibit tumor formation in different organ environments and that gene delivery of endostatin into even a minority of tumor cells may be an effective strategy to prevent progression of micrometastases to macroscopic disease.
Cancer Res 1999 Dec 15
PMID:Mouse endostatin inhibits the formation of lung and liver metastases. 1062 20

Endostatin, a carboxyl-terminal fragment of collagen XVIII is known as an anti-angiogenic agent, that specifically inhibits the proliferation of endothelial cell and the growth of several primary tumor. We report here the purification and characterization of the recombinant murine endostatin (rmEndostatin) which was expressed in a prokaryotic expression system. This rmEndostatin has similar physiochemical properties of yeast-produced recombinant endostatin, and it also specifically inhibits the proliferation and migration of bovine capillary endothelial cells stimulated by basic fibroblast growth factor. The biological activity of rmEndostatin was also shown by its anti-angiogenic ability on the chorioallantoic membrane of chick embryo in vivo. In this article, we demonstrate the refolding and purification of rmEndostatin, expressed using E. coli system, to a biologically active and soluble form. In addition, these results confirm the activity of endostatin as a potent anti-angiogenic agent.
Exp Mol Med 1999 Dec 31
PMID:Purification and characterization of recombinant murine endostatin in E. coli. 1063 Mar 74


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