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Archivum Immunologiae Et Therapiae... Feb 2010The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most... (Review)
Review
The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.
Topics: Diabetic Nephropathies; Gene Expression Regulation, Enzymologic; Glomerular Basement Membrane; Glucuronidase; Heparan Sulfate Proteoglycans; Humans; Kidney Glomerulus; Oligosaccharides; Proteinuria; Signal Transduction
PubMed: 20049646
DOI: 10.1007/s00005-009-0061-6 -
Annals of Oncology : Official Journal... Jun 2010Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.
PATIENTS AND METHODS
We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks
RESULTS
Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%.
CONCLUSIONS
The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Dose-Response Relationship, Drug; Glucuronidase; Humans; Male; Middle Aged; Neoplasm Metastasis; Oligosaccharides; Prostatic Neoplasms; Taxoids; Treatment Failure
PubMed: 19917571
DOI: 10.1093/annonc/mdp524 -
Clinical and Experimental Pharmacology... Apr 20101. The heparan sulphate proteoglycan glypican-1 is a major high-affinity ligand of the Slit proteins. 2. Messenger RNA for both Slit-2 and glypican-1 is strongly...
1. The heparan sulphate proteoglycan glypican-1 is a major high-affinity ligand of the Slit proteins. 2. Messenger RNA for both Slit-2 and glypican-1 is strongly upregulated and coexpressed in the reactive astrocytes of injured adult brain, suggesting a possible function of Slit proteins and glypican-1 in the adult central nervous system as significant components of the inhibitory environment that prevents axonal regeneration after injury. 3. Based on the hypothesis that adverse effects on axonal regeneration may be due to a glypican-Slit complex or the retention of glypican-binding C-terminal proteolytic processing fragments of Slit at the injury site, we used ELISA to examine a number of small molecules and low molecular weight heparin analogues for their ability to inhibit glypican-Slit interactions. 4. Our studies have led to the identification of several potent inhibitors with a favourable therapeutic profile that can now be tested in a spinal cord injury model. Among the most promising of these are a low molecular weight heparin produced by periodate oxidation and having no significant anticoagulant activity, the chemically sulphonated yeast-derived phosphomannan PI-88 and a number of randomly derivatized water-soluble sulphated dextrans.
Topics: Anticoagulants; Dalteparin; Dextran Sulfate; Drug Design; Enoxaparin; Fondaparinux; Glycoproteins; Glypicans; Heparin, Low-Molecular-Weight; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Nerve Tissue Proteins; Oligosaccharides; Osmolar Concentration; Oxidation-Reduction; Periodic Acid; Polysaccharides; Protein Binding; Protein Isoforms; Recombinant Fusion Proteins; Spinal Cord Injuries
PubMed: 19843094
DOI: 10.1111/j.1440-1681.2009.05318.x -
Glycobiology Feb 2010Heparan sulfates (HS) bind a diversity of protein ligands on the cell surface and in the extracellular matrix and thus can modulate cell signaling. The state of...
Heparan sulfates (HS) bind a diversity of protein ligands on the cell surface and in the extracellular matrix and thus can modulate cell signaling. The state of sulfation in glucosamines and uronic acids within the chains strongly influences their binding. We have previously cloned and characterized two human extracellular endoglucosamine 6-sulfatases, HSulf-1 and HSulf-2, which selectively liberate the 6-O sulfate groups on glucosamines present in N, 6-O, and 2-O trisulfated disaccharides of intact HS and heparins. These enzymes serve important roles in development and are upregulated in a number of cancers. To determine whether the Sulfs act on the trisulfated disaccharides that exist on the cell surface, we expressed HSulfs in cultured cells and performed a flow cytometric analysis with the RB4CD12, an anti-HS antibody that recognizes N- and O-sulfated HS saccharides. The endogenously expressed level of the cell surface RB4CD12 epitope was greatly diminished in CHO, HEK293, and HeLa cells transfected with HSulf-1 or HSulf-2 cDNA. In correspondence with the RB4CD12 finding, the N, 6-O, and 2-O trisulfated disaccharides of the HS isolated from the cell surface/extracellular matrix were dramatically reduced in the Sulf-expressed HEK293 cells. We then developed an ELISA and confirmed that the RB4CD12 epitope in immobilized heparin was degraded by purified recombinant HSulf-1 and HSulf-2, and conditioned medium (CM) of MCF-7 breast carcinoma cells, which contain a native form of HSulf-2. Furthermore, HSulf-1 and HSulf-2 exerted activity against the epitope expressed on microvessels of mouse brains. Both HSulf activities were potently inhibited by PI-88, a sulfated heparin mimetic with anti-cancer activities. These findings provide new strategies for monitoring the extracellular remodeling of HS by Sulfs during normal and pathophysiological processes.
Topics: Animals; Brain; Cells, Cultured; Cloning, Molecular; Cricetinae; Cricetulus; Enzyme Inhibitors; Epitopes; Heparitin Sulfate; Humans; Mice; Microvessels; Oligosaccharides; Recombinant Proteins; Structure-Activity Relationship; Sulfatases; Sulfotransferases
PubMed: 19822709
DOI: 10.1093/glycob/cwp159 -
Analytical Biochemistry Jan 2010The role that heparanase plays during metastasis and angiogenesis in tumors makes it an attractive target for cancer therapeutics. Despite this enzyme's significance,...
The role that heparanase plays during metastasis and angiogenesis in tumors makes it an attractive target for cancer therapeutics. Despite this enzyme's significance, most of the assays developed to measure its activity are complex. Moreover, they usually rely on labeling variable preparations of the natural substrate heparan sulfate, making comparisons across studies precarious. To overcome these problems, we have developed a convenient assay based on the cleavage of the synthetic heparin oligosaccharide fondaparinux. The assay measures the appearance of the disaccharide product of heparanase-catalyzed fondaparinux cleavage colorimetrically using the tetrazolium salt WST-1. Because this assay has a homogeneous substrate with a single point of cleavage, the kinetics of the enzyme can be reliably characterized, giving a K(m) of 46 microM and a k(cat) of 3.5 s(-1) with fondaparinux as substrate. The inhibition of heparanase by the published inhibitor, PI-88, was also studied, and a K(i) of 7.9 nM was determined. The simplicity and robustness of this method, should, not only greatly assist routine assay of heparanase activity but also could be adapted for high-throughput screening of compound libraries, with the data generated being directly comparable across studies.
Topics: Colorimetry; Enzyme Assays; Enzyme Inhibitors; Fondaparinux; Glucuronidase; Humans; Kinetics; Oligosaccharides; Polysaccharides; Reducing Agents; Time Factors
PubMed: 19748475
DOI: 10.1016/j.ab.2009.09.007 -
Cancer Chemotherapy and Pharmacology Mar 2010The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of...
PURPOSE
The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer.
METHODS
A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery.
RESULTS
Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%).
CONCLUSIONS
This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.
Topics: Adult; Aged; Algorithms; Area Under Curve; Enzyme Inhibitors; Female; Glucuronidase; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Neoplasms; Oligosaccharides; Time Factors; Young Adult
PubMed: 19633850
DOI: 10.1007/s00280-009-1080-z -
Journal of Hepatology May 2009
Topics: Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Combined Modality Therapy; Endpoint Determination; Enzyme Inhibitors; Humans; Liver Neoplasms; Oligosaccharides; Patient Selection; Treatment Outcome
PubMed: 19329214
DOI: 10.1016/j.jhep.2009.02.016 -
Journal of Hepatology May 2009Hepatocellular carcinoma recurrence after curative treatment adversely influences clinical outcome. It is important to explore adjuvant therapies. This phase II/stage 1... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND/AIMS
Hepatocellular carcinoma recurrence after curative treatment adversely influences clinical outcome. It is important to explore adjuvant therapies. This phase II/stage 1 multi-center, randomized trial investigated the safety, optimal dosage and preliminary efficacy of PI-88, a novel heparanase inhibitor, in the setting of post-operative recurrence of HCC according to a Simon's 2-stage design.
METHODS
Three groups were included: one untreated arm (Group A) and two PI-88 arms (Group B: 160 mg/day; Group C: 250 mg/day). Treatment groups received PI-88 over nine 4-week treatment cycles, followed by a 12-week treatment-free period. Safety and optimal dosage were assessed.
RESULTS
Overall, 172 patients were randomized and 168 were included in the intention-to-treat (ITT) population. Treatment-related adverse effects included cytopenia, injection site hemorrhage, PT prolongation, etc. Four serious adverse events were possibly related to PI-88 treatment. One (1.8%) group B patients and six (10.5%) group C had hepatotoxicity-related withdrawals. Among the ITT population, 29 patients (50%) in Group A, 35 (63%) in Group B, and 22 (41%) in Group C remained recurrence-free at completion. Calculated T(1) value suggested 160 mg/day treatment satisfied the criteria for the next stage of the trial.
CONCLUSIONS
PI-88 at 160 mg/day is optimal and safe, and shows preliminary efficacy as an adjunct therapy for post-operative HCC.
Topics: Adult; Aged; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Glucuronidase; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Oligosaccharides; Treatment Outcome
PubMed: 19303160
DOI: 10.1016/j.jhep.2008.12.023 -
Biochemical and Biophysical Research... Mar 2009Retinal leukostasis, mediated by intracellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF), has been implicated in the pathogenesis of...
Retinal leukostasis, mediated by intracellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF), has been implicated in the pathogenesis of early diabetic retinopathy. Phosphomannopentaose sulfate (PI-88) is a highly sulfonated oligosaccharide which inhibits heparanase activity and competes with heparan sulfate binding to growth factors. In this study, we evaluated whether PI-88 could inhibit retinal leukostasis in strepotzotocin(STZ)-induced diabetic rat and elucidated the possible mechanisms. Diabetes was induced in Sprague-Dawley rats by intraperitoneal injection (i.p.) of STZ. Three months after induction, diabetic rats were administered PI-88 (25 mg/kg body weight) or vehicle solution daily via i.p. for 14 consecutive days. Leukostasis was analyzed on retinal flatmounts by concanavalin A and CD45 immunofluorescence staining. Retinal function was analyzed by electroretinography (ERG). ICAM-1 and VEGF levels in retinas were studied by Western blot and enzyme-linked immunosorbent assay (ELISA) respectively. The systemic administration of PI-88, but not vehicle, significantly decreased the number of adherent leukocytes in retinas by 52.24% (P<0.001) and led to significant preservation (about 50%, P<0.001) of scotopic ERG a- and b-wave amplitudes in treated diabetic rats as compared to those of diabetic control rats. These changes were associated with downregulation of ICAM-1 (45%, P<0.001) and VEGF (26.83+/-2.01 versus 40.8+/-3.24 pg/mg, P<0.01) in retinas of PI-88 treated diabetic rats as compared to those of diabetic control rats. PI-88 significantly inhibited retinal leukostasis and reversed retinal dysfunction by a mechanism that may include decreased ICAM-1 and VEGF expression in diabetic rats. Our data suggests that PI-88 is a promising agent for the treatment of diabetic retinopathy.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Down-Regulation; Electroretinography; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Leukostasis; Oligosaccharides; Rats; Rats, Sprague-Dawley; Retina; Vascular Endothelial Growth Factor A
PubMed: 19250642
DOI: 10.1016/j.bbrc.2009.01.092 -
[Zhonghua Yan Ke Za Zhi] Chinese... Sep 2008To probe the intervention and mechanism of the inhibitor of heparanase (PI-88) on the experimental CNV model .
OBJECTIVE
To probe the intervention and mechanism of the inhibitor of heparanase (PI-88) on the experimental CNV model .
METHODS
Experimental CNV was induced by laser photocoagulation in 29 mail (Brown Norway) BN rats (647 nm wave length Krypton laser, 360 mW power, 50 microm spot size, 0.05 second duration), and randomly divided into vacant control group, physiologic saline control group, preventive group and treated group, another 3 rats were acted as normal group, 15 days continuous intraperitoneal injection of PI-88 (25 mg kg(-1) d(-1) was administrated in preventive group (PI-88 was administered the same day as photocoagulation) and treated group (PI-88 was administered 1 week after photocoagulation when CNV had been formed), for the physiologic saline control group, PI-88 was replaced by physiologic saline. To comprehensively evaluate the effect of PI-88 on the CNV by the quantitation of CNV area marked by FITC-dextran in choroid-sclera flat mounts, fluorescence fundus angiography and histopathology; the changes of HPA expression were surveyed by western blot and immunohistochemistry.
RESULTS
CNV area of preventive group and treated group decreased 52.1% and 53.8% respectively at the time point of 3 weeks after photocoagulation; the relative thickness of CNV membrane in eyes of treated group had been decreased 46% as that of control group by histopathology; CNV occurrenced 1 week after photocoagulation both in the control group and preventive group, while the fluorescein leakage of the preventive group had been inhibited significantly; 3 weeks after photocoagulation, there had been 7 days discontinuation for the prevent group, the fluorescein leakage did not enhanced, while there had been 15 days continuous administration for the treated group, the fluorescein leakage had been decreased significantly compared to the time point of 2 week; western blot showed that the relative expressed levels of HPA protein in both preventive and treated group decreased; HPA displayed distribution at the leading edge of CNV membrane migrating toward inner retina and the vascular tissue by immunohistochemistry, the expression of HPA was inhibited significantly in treated group.
CONCLUSION
PI-88 may not only prevent CNV in certain degree, but also make it partially subsidize for the existed CNV, and the effect is associated with the inhibition of HPA production.
Topics: Animals; Choroidal Neovascularization; Disease Models, Animal; Male; Oligosaccharides; Rats; Rats, Inbred BN
PubMed: 19175161
DOI: No ID Found