-
Clinical and Applied... Apr 2001PI-88 is a potent antiproliferative agent, which is developed for various indications in cancer. This agent is obtained from yeast fermentation and is primarily composed...
PI-88 is a potent antiproliferative agent, which is developed for various indications in cancer. This agent is obtained from yeast fermentation and is primarily composed of pentamannose and tetramannose oligosaccharide units. PI-88 is capable of producing anticoagulant effects, which are mediated by heparin cofactor II. The purpose of this study was to determine the anticoagulant properties of PI-88 in native whole blood, freshly drawn from human volunteers, supplemented with PI-88 at various concentrations (0-100 microg/mL). Whole blood activated clotting time (ACT) was measured using Hemochron instruments. PI-88 produced a strong anticoagulant effect at 100 microg/mL (479.0+/-59.5 sec). This anticoagulant effect was comparable to that observed in interventional cardiology and open-heart surgery. At the lower level, PI-88 produced concentration-dependent effects on ACT. Using thromboelastographic techniques (TEG), the effect of PI-88 was measured in terms of various parameters. PI-88 produced potent anticoagulant effects in the TEG studies. At the concentration of 25 microg/mL, it produced a complete anticoagulant effect in whole blood. Whole blood samples supplemented with PI-88 showed a concentration-dependent decrease in the generation of various markers of clotting activation. These results clearly suggest that PI-88 exerts an anticoagulant effect in whole blood. Because of the low-molecular-weight nature and a novel mechanism of action, this new drug may be considered for further development, particularly in cancer patients.
Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation Tests; Dose-Response Relationship, Drug; Humans; Oligosaccharides; Thrombelastography
PubMed: 11292193
DOI: 10.1177/107602960100700212 -
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 -
Virology Oct 2007Herpes simplex virus type 1 variants selected by virus propagation in cultured cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these...
Herpes simplex virus type 1 variants selected by virus propagation in cultured cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these variants were substantially resistant to the presence of PI-88 during their initial infection of cells and/or their cell-to-cell spread. Nucleotide sequence analysis revealed that the deletion of amino acids 33-116 of gC but not lack of gC expression provided the virus with selective advantage to infect cells in the presence of PI-88. Purified gC (Delta33-116) was more resistant to PI-88 than unaltered protein in its binding to cells. Alterations that partly contributed to the virus resistance to PI-88 in its cell-to-cell spread activity were amino acid substitutions Q27R in gD and R770W in gB. These results suggest that PI-88 targets several distinct viral glycoproteins during the course of initial virus infection and cell-to-cell spread.
Topics: Amino Acid Sequence; Amino Acids; Animals; DNA, Viral; Drug Resistance, Microbial; Herpesvirus 1, Human; Humans; Mutation; Oligosaccharides; Tumor Cells, Cultured; Viral Envelope Proteins
PubMed: 17604805
DOI: 10.1016/j.virol.2007.05.040 -
Neoplasia (New York, N.Y.) Nov 2010Heparanase-1 (HPR1), an endoglycosidase that specifically degrades heparan sulfate (HS) proteoglycans, is overexpressed in a variety of malignancies. Our present study...
Heparanase-1 (HPR1), an endoglycosidase that specifically degrades heparan sulfate (HS) proteoglycans, is overexpressed in a variety of malignancies. Our present study sought to determine whether oncogene BRAF and RAS mutations lead to increased HPR1 expression. Reverse transcription-polymerase chain reaction analysis revealed that HPR1 gene expression was increased in HEK293 cells transiently transfected with a mutant BRAF or RAS gene. Flow cytometric analysis revealed that B-Raf activation led to loss of the cell surface HS, which could be blocked by two HPR1 inhibitors: heparin and PI-88. Cotransfection of a BRAF or RAS mutant gene with HPR1 promoter-driven luciferase reporters increased luciferase reporter gene expression in HEK293 cells. Knockdown of BRAF expression in a BRAF-mutated KAT-10 tumor cell line led to the suppression of HPR1 gene expression, subsequently leading to increased cell surface HS levels. Truncational and mutational analyses of the HPR1 promoter revealed that the Ets-relevant elements in the HPR1 promoter were critical for BRAF activation-induced HPR1 expression. Luciferase reporter gene expression driven by a four-copy GA binding protein (GABP) binding site was significantly lower in BRAF siRNA-transfected KAT-10 cells than in the control siRNA-transfected cells. We further showed that BRAF knockdown led to suppression of the expression of the GABPβ, an Ets family transcription factor involved in regulating HPR1 promoter activity. Taken together, our study suggests that B-Raf kinase activation plays an important role in regulating HPR1 expression. Increased HPR1 expression may contribute to the aggressive behavior of BRAF-mutated cancer.
Topics: Binding Sites; Blotting, Western; Cell Line, Tumor; Enzyme Activation; GA-Binding Protein Transcription Factor; Gene Expression Regulation, Enzymologic; Glucuronidase; HEK293 Cells; Heparin; Heparitin Sulfate; Humans; Luciferases; Microscopy, Fluorescence; Mutation; Oligosaccharides; Promoter Regions, Genetic; Proto-Oncogene Proteins B-raf; RNA Interference; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; ras Proteins
PubMed: 21076620
DOI: 10.1593/neo.10790