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World Journal of Gastroenterology Aug 2014To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year... (Observational Study)
Observational Study Randomized Controlled Trial
AIM
To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.
METHODS
A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival.
RESULTS
PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence.
CONCLUSION
Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.
Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Enzyme Inhibitors; Female; Glucuronidase; Humans; Liver Neoplasms; Male; Middle Aged; Oligosaccharides; Risk Factors; Survival Analysis; Taiwan; Time Factors; Treatment Outcome
PubMed: 25170226
DOI: 10.3748/wjg.v20.i32.11384 -
Antimicrobial Agents and Chemotherapy Feb 2016Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface...
Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo- and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo- and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle-disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses.
Topics: Administration, Intravaginal; Animals; Antiviral Agents; Disease Models, Animal; Female; Herpes Genitalis; Herpesvirus 2, Human; Lipids; Mice, Inbred C57BL; Oligosaccharides; Saponins; Virion
PubMed: 26643323
DOI: 10.1128/AAC.02132-15 -
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 -
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 -
Expert Opinion on Investigational Drugs Nov 2008Growth factors that stimulate angiogenesis are vital in tumor development and maintenance. Inhibitors of angiogenesis are emerging as key elements in anticancer...
Growth factors that stimulate angiogenesis are vital in tumor development and maintenance. Inhibitors of angiogenesis are emerging as key elements in anticancer treatments, and now antibodies and small molecule kinase inhibitors are approved in the treatment of a variety of solid tumors. These have shown modest but statistically significant benefit in colon, breast and lung cancers. PI-88 has a novel mechanism of action compared to the drugs on the market today. By inhibiting heparanase, PI-88 blocks angiogenesis on several different cellular and biological levels. Promising results from Phase I/II trials are being seen with PI-88 in a variety of tumor types including melanoma and hepatocellular carcinoma. However, the development of antibody-induced thrombocytopenia has limited its use in some patients.
Topics: Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Humans; Neoplasms; Oligosaccharides; Signal Transduction; Treatment Outcome
PubMed: 18922112
DOI: 10.1517/13543784.17.11.1769 -
Thrombosis Research Aug 2001In this study, 17 sulfated oligosaccharides were assessed by the activated partial thromboplastin time (APTT) test for their anticoagulant activity and nine were found...
In this study, 17 sulfated oligosaccharides were assessed by the activated partial thromboplastin time (APTT) test for their anticoagulant activity and nine were found to exhibit significant activity. Chain length, monosaccharide makeup, and linkage all appear to be critical factors in determining anticoagulant activity, with the most active compounds being five- to sixfold less potent than unfractionated heparin (UFH). Phosphomannopentaose sulfate (PI-88), one of the most active sulfated oligosaccharides and a promising anticancer drug, was selected for further study. PI-88 gave a more linear APTT dose-response curve and displayed less patient-to-patient variation than UFH, with its activity being neutralised by protamine sulfate. However, PI-88 showed considerable species-to-species variation in its anticoagulant effect. It was found that PI-88 acted as an anticoagulant by enhancing the ability of heparin cofactor II (HCII) to inhibit thrombin, and did not act via antithrombin III (AT-III) in either inhibiting Factor Xa or thrombin. PI-88 also mildly prolonged the prothrombin time (PT), whilst it had no platelet pro-aggregatory activity, nor did it demonstrate direct fibrinolytic activity. Thus, PI-88 represents a potential antithrombotic agent deserving further study.
Topics: Animals; Anticoagulants; Antineoplastic Agents; Antithrombin III; Blood Coagulation; Drug Synergism; Heparin; Heparin Cofactor II; Humans; Oligosaccharides; Partial Thromboplastin Time; Species Specificity; Structure-Activity Relationship; Sulfuric Acid Esters; Thrombin
PubMed: 11562342
DOI: 10.1016/s0049-3848(01)00314-0 -
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 -
Bioorganic & Medicinal Chemistry Jan 2008A stepwise synthetic route to the mannooligosaccharides from the neutral fraction of Pichia holstii phosphomannan hydrolysate, including a tetrasaccharylamine component,...
A stepwise synthetic route to the mannooligosaccharides from the neutral fraction of Pichia holstii phosphomannan hydrolysate, including a tetrasaccharylamine component, was developed using only two or three readily available d-mannose building blocks. These compounds were sulfonated to give the corresponding sulfated oligosaccharides which are closely related to the constituents of the anticancer agent PI-88. The synthetic approach is well suited to the preparation of analogues as demonstrated by the synthesis of a series of (1-->3)-linked mannooligosaccharides. The inhibitory activity of the sulfated oligosaccharides against heparanase was determined using a Microcon ultrafiltration assay. The tetra- and pentasaccharides were potent competitive inhibitors of heparanase (K(i)=200-280nM) whilst the shorter di- and trisaccharides were partial competitive inhibitors and did not completely inhibit the enzyme even at very high concentrations.
Topics: Angiogenesis Inhibitors; Combinatorial Chemistry Techniques; Dose-Response Relationship, Drug; Glucuronidase; Humans; Molecular Structure; Oligosaccharides; Pichia; Sulfuric Acid Esters
PubMed: 17967543
DOI: 10.1016/j.bmc.2007.10.044 -
Bone Oct 2008Endochondral bone formation is a highly orchestrated process involving coordination among cell-cell, cell-matrix and growth factor signaling that eventually results in...
Endochondral bone formation is a highly orchestrated process involving coordination among cell-cell, cell-matrix and growth factor signaling that eventually results in the production of mineralized bone from a cartilage template. Chondrogenic and osteogenic differentiation occur in sequence during this process, and the temporospatial patterning clearly requires the activities of heparin binding growth factors and their receptors. Heparanase (HPSE) plays a role in osteogenesis, but the mechanism by which it does so is incompletely understood. We used a combination of ex vivo and in vitro approaches and a well described HPSE inhibitor, PI-88 to study HPSE in endochondral bone formation. In situ hybridization and immunolocalization with HPSE antibodies revealed that HPSE is expressed in the peri-chondrium, peri-osteum, and at the chondro-osseous junction, all sites of key signaling events and tissue morphogenesis. Transcripts encoding Hpse also were observed in the pre-hypertrophic zone. Addition of PI-88 to metatarsals in organ culture reduced growth and suggested that HPSE activity aids the transition from chondrogenic to osteogenic processes in growth of long bones. To study this, we used high density cultures of ATDC5 pre-chondrogenic cells grown under conditions favoring chondrogenesis or osteogenesis. Under chondrogenic conditions, HPSE/Hpse was expressed at high levels during the mid-culture period, at the onset of terminal chondrogenesis. PI-88 addition reduced chondrogenesis and accelerated osteogenesis, including a dramatic up-regulation of osteocalcin levels. In normal growth medium, addition of PI-88 reduced migration of ATDC-5 cells, suggesting that HPSE facilitates cartilage replacement by bone at the chondro-osseous junction by removing the HS component of proteoglycans, such as perlecan/HSPG2, that otherwise prevent osteogenic cells from remodeling hypertrophic cartilage.
Topics: Animals; Cell Line, Tumor; Cell Movement; Chondrocytes; Chondrogenesis; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation, Enzymologic; Glucuronidase; Immunoblotting; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Inbred C57BL; Oligosaccharides; Organ Culture Techniques; Osteogenesis
PubMed: 18589009
DOI: 10.1016/j.bone.2008.05.022 -
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