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Biology of Reproduction Sep 2007Embryo implantation is a complex process that involves interactions between cell-surface and extracellular components of the blastocyst and the uterus, including...
Embryo implantation is a complex process that involves interactions between cell-surface and extracellular components of the blastocyst and the uterus, including blastocyst adhesion to the uterine luminal epithelium, epithelial basement membrane penetration and stromal extracellular matrix remodeling, angiogenesis, and decidualization. These processes all involve interactions with heparan sulfate (HS) proteoglycans, which harbor various growth factors and cytokines and support cell adhesion. Heparanase (HPSE) is an endo-beta-glucuronidase that cleaves HS at specific sites. HPSE also can act as an adhesion molecule independent of its catalytic activity. Thus, HPSE is a multifunctional molecule contributing to and modulating HS-dependent processes. Exogenously added HPSE improves embryo implantation in mice; however, no information is available regarding the normal pattern of HPSE expression and activity during the implantation process in any system. Using several approaches, including real-time RT-PCR, in situ hybridization, and immunohistochemistry, we determined that uterine HPSE expression increases dramatically during early pregnancy in mice. Heparanase mRNA and protein were primarily expressed in decidua and were rapidly induced at the implantation site. Uterine HPSE activity was characterized and demonstrated to increase >40-fold during early pregnancy. Finally, we demonstrate that the HPSE inhibitor PI-88 severely inhibits embryo implantation in vivo. Collectively, these results indicate that HPSE plays a role in blastocyst implantation and complements previous studies showing a role for HS-dependent interactions in this process.
Topics: Animals; Cell Line; Decidua; Embryo Implantation; Endometrium; Enzyme Inhibitors; Female; Fluorescent Antibody Technique, Indirect; Glucuronidase; Heparan Sulfate Proteoglycans; Male; Mice; Mice, Inbred ICR; Nucleic Acid Hybridization; Oligosaccharides; Pregnancy; Pregnancy, Animal; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 17507691
DOI: 10.1095/biolreprod.107.061317 -
Clinical Cancer Research : An Official... Sep 2006PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to...
PURPOSE
PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study.
EXPERIMENTAL DESIGN
This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2).
RESULTS
Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months.
CONCLUSION
The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.
Topics: Adult; Aged; Antibody Formation; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Renal Cell; Colorectal Neoplasms; Female; Fibroblast Growth Factors; Glucuronidase; Humans; Leiomyosarcoma; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasms; Oligosaccharides; Partial Thromboplastin Time; Vascular Endothelial Growth Factor A
PubMed: 17000682
DOI: 10.1158/1078-0432.CCR-05-2423 -
Yao Xue Xue Bao = Acta Pharmaceutica... Oct 2005
Review
Topics: Animals; Cell Proliferation; Gene Expression Regulation, Enzymologic; Glucuronidase; Humans; Myocytes, Smooth Muscle; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligosaccharides
PubMed: 16408800
DOI: No ID Found -
Journal of Medicinal Chemistry Dec 2005The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its...
The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.
Topics: Angiogenesis Inhibitors; Animals; Antiviral Agents; Blood Platelets; Cells, Cultured; Chlorocebus aethiops; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Glucuronidase; Herpesvirus 1, Human; Humans; Male; Oligosaccharides; Rats; Rats, Sprague-Dawley; Surface Plasmon Resonance; Vascular Endothelial Growth Factor A
PubMed: 16366604
DOI: 10.1021/jm050618p -
Antiviral Research Jan 2006Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This... (Comparative Study)
Comparative Study
Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This raises the possibility of the application of HS mimetics in antiviral therapy. We have evaluated the antiviral effect of the sulfated polysaccharides, suramin, pentosan polysulfate (PPS) and PI-88, which are currently approved or in trial for clinical use, against dengue virus (DEN) and the encephalitic flaviviruses, Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus. A flow cytometry-based method for the measurement of inhibition of virus infectivity was developed, which showed the in vitro antiviral activity of the three compounds, albeit with differences in efficiency which were virus-dependent. The 50% effective concentration (EC(50)) values for DEN inhibition were in the order: PPS
Topics: Animals; Antiviral Agents; Cell Line; Dengue; Dengue Virus; Disease Models, Animal; Drug Evaluation, Preclinical; Encephalitis Viruses, Japanese; Encephalitis, Arbovirus; Female; Flavivirus Infections; Heparitin Sulfate; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligosaccharides; Pentosan Sulfuric Polyester; Suramin; Treatment Outcome
PubMed: 16309754
DOI: 10.1016/j.antiviral.2005.08.006 -
Bioorganic & Medicinal Chemistry Dec 2004Methods for the stereoselective synthesis of alpha-(1-->2)- and alpha-(1-->3)-linked 6(II)-O-phosphomannobiosides were developed. Two strategies were successfully...
Methods for the stereoselective synthesis of alpha-(1-->2)- and alpha-(1-->3)-linked 6(II)-O-phosphomannobiosides were developed. Two strategies were successfully employed: a D-mannosyl acceptor was coupled with a phosphorylated D-mannosyl trichloroacetimidate donor, or alternatively with a differentially 6-O-protected D-mannosyl trichloroacetimidate donor which, after glycosylation, was selectively deprotected and phosphorylated. Two target phosphomannobiosides intended for use in SAR studies of the antiangiogenic drug candidate PI-88, 2-O-(6-O-phospho-alpha-D-mannopyranosyl)-D-mannopyranose and methyl 3-O-(6-O-phospho-alpha-D-mannopyranosyl)-alpha-D-mannopyranoside, were synthesized. The former is a minor component of the side-chain repeating unit of the extracellular phosphomannan of Pichia (Hansenula) holstii NRRL Y-2448, whilst the latter represents a nonreducing end fragment of the phosphomannan.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Disaccharides; Mannans; Oligosaccharides; Pichia; Structure-Activity Relationship; Sugar Phosphates
PubMed: 15519152
DOI: 10.1016/j.bmc.2004.09.005 -
Journal of the American Society of... Nov 2004The beta-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side...
The beta-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side chains of heparan sulfate proteoglycans (HSPG) within the glomerular basement membrane (GBM). A loss of the negatively charged HSPG may result in alteration of the permselective properties of the GBM, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. This study examined the effect of PI-88, a sulfated oligosaccharide heparanase inhibitor, on renal function, glomerular ultrastructure, and proteinuria. Continuous PI-88 infusion at 25 mg/kg per d did not adversely affect animal behavior, growth, or GFR. Cortical tubular vacuolation, however, was observed by light microscopy, and GBM thickness was significantly reduced in these animals (P < 0.0002). Tissue distribution studies using [(35)S]-labeled PI-88 revealed high levels of radioactivity in the kidney after a single subcutaneous injection of 25 mg/kg, suggesting protracted accumulation; moreover, active PI-88 was detected in urine. In passive Heymann nephritis, PI-88 delivered as a continuous infusion at 25 mg/kg per d significantly reduced autologous-phase proteinuria, at day 14 (P < 0.009), in the absence of altered sheep antibody deposition, C5b-9 deposition, and circulating rat anti-sheep antibody titers. Glomerular vascular endothelial growth factor and fibroblast growth factor expression was unaffected by PI-88 administration. However, PI-88 administration significantly prevented glomerular HSPG loss as demonstrated by quantitative immunofluorescence studies (P < 0.0001) in the absence of altered agrin distribution. These data therefore confirm the importance of heparanase in the development of proteinuria.
Topics: Animals; Autoradiography; Complement Membrane Attack Complex; Fluorescent Antibody Technique; Glomerulonephritis; Heparan Sulfate Proteoglycans; Immunoglobulin G; Kidney; Kidney Glomerulus; Microscopy, Electron; Oligosaccharides; Proteinuria; Rats; Rats, Sprague-Dawley; Sheep
PubMed: 15504941
DOI: 10.1097/01.ASN.0000142426.55612.6D -
Antiviral Research Jul 2004Although a number of sulfated polysaccharides have been shown to inhibit infection of cells by herpes simplex virus (HSV), little is known about their effects on the...
Although a number of sulfated polysaccharides have been shown to inhibit infection of cells by herpes simplex virus (HSV), little is known about their effects on the cell-to-cell spread of the virus. These compounds act by inhibiting the virus binding to cells, and their antiviral potencies usually increase with increasing molecular weight and sulfation density. We report that the low molecular weight HS-mimetic, PI-88, which is a mixture of highly sulfated mannose-containing di- to hexa-saccharides, inhibited HSV infection of cells and cell-to-cell spread of HSV-1 and HSV-2. Compared to a relatively large heparin polysaccharide, PI-88 demonstrated weaker inhibition of HSV infectivity but more efficient reduction of cell-to-cell spread of HSV. A tetrasaccharide fraction of PI-88 was the minimum fragment necessary to inhibit HSV-1 infectivity, while a trisaccharide was sufficient to reduce cell-to-cell spread. A reduction in HSV lateral spread was also observed in cells incubated with another low molecular weight compound, pentosan polysulfate but not with much larger polysaccharide chondroitin sulfate E. Some differences as regards the effects of PI-88, heparin, protamine, poly-L-lysine and sodium chlorate on intercellular spread of HSV-1 and HSV-2 were found. We conclude that structurally different sulfated oligosaccharides are preferred for inhibition of HSV infectivity and the cell-to-cell spread. The latter was efficiently inhibited by a relatively small but densely sulfated PI-88 oligosaccharide, very likely due to the capability of the compound to access the narrow intercellular space.
Topics: Alphaherpesvirinae; Antiviral Agents; Cell Line; Heparitin Sulfate; Molecular Weight; Oligosaccharides; Sulfates
PubMed: 15196816
DOI: 10.1016/j.antiviral.2004.01.001 -
Carbohydrate Research Apr 2004An efficient and convergent synthesis of a regioselectively 6(V)-sulfated mannopentasaccharide derivative 1c, octyl...
An efficient and convergent synthesis of a regioselectively 6(V)-sulfated mannopentasaccharide derivative 1c, octyl 6-O-sulfo-alpha-D-mannopyranosyl-(1-->3)-alpha-D-mannopyranosyl-(1-->3)-alpha-d-mannopyranosyl-(1-->3)-alpha-D-mannopyranosyl-(1-->2)-alpha-D-mannopyranoside, was achieved by a '3 + 2' strategy. The target was designed to mimic the promising anticancer agent PI-88 and was obtained from the building blocks, octyl 3,4,6-tri-O-benzoyl-alpha-D-mannopyranoside, allyl 2,4,6-tri-O-benzoyl-3-O-(4-methoxybenzyl)-alpha-D-mannopyranoside, and 6-O-acetyl-2,3,4-tri-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate (11), under TMSOTf-catalyzed glycosylation conditions. Compound 1c displays a mild anti-angiogenic activity based on a chorioallantoic membrane (CAM) model study.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carbohydrate Conformation; Carbohydrate Sequence; Glycosylation; Magnetic Resonance Spectroscopy; Mannose; Models, Chemical; Molecular Sequence Data; Oligosaccharides; Polysaccharides; Sulfur
PubMed: 15063205
DOI: 10.1016/j.carres.2004.01.020 -
Cardiovascular Drug Reviews 2004The sulfated oligosaccharide PI-88 is a potent antiangiogenic, antitumor and anti-metastatic agent derived from yeast. It is primarily composed of sulfated... (Review)
Review
The sulfated oligosaccharide PI-88 is a potent antiangiogenic, antitumor and anti-metastatic agent derived from yeast. It is primarily composed of sulfated phosphomannopentaose and phosphomannotetraose oligosaccharide units and is presently under evaluation in Phase II clinical trials for anticancer efficacy. PI-88 inhibits the heparan sulfate-degrading enzyme heparanase, exhibits antiangiogenic activity and has anticoagulant properties mediated by heparin cofactor II. It also inhibits vascular smooth muscle cell proliferation, kinase signalling and arterial intimal thickening following balloon injury. Many heparan sulfate-binding growth factors require heparan sulfate as a co-receptor in order to effectively deliver growth signals to cells. Thus, the antiangiogenic and antirestenotic activity of PI-88 may be at least partially due to this highly sulfated oligosaccharide competing with the interaction of growth factors, such as FGF-2 and VEGF, with cell surface heparan sulfate. This heparan sulfate mimetic has, therefore, multiple functions and therapeutic potential in a variety of vascular disorders.
Topics: Angiogenesis Inhibitors; Anticoagulants; Antineoplastic Agents; Coronary Restenosis; Heparitin Sulfate; Humans; Molecular Mimicry; Oligosaccharides
PubMed: 14978514
DOI: 10.1111/j.1527-3466.2004.tb00127.x