title: Role of polymorphonuclear leukocytes, nitric oxide synthase, and cyclooxygenase in vascular permeability changes induced by C5a agonist peptides.
abstract: Tumor responses to radioimmunotherapy combined with peptide agonists of human C5a anaphylatoxin such as GCGYSFKPMPLaR (C5aAP) are two- to four-fold better, depending on the dose of C5aAP, than responses to radioimmunotherapy alone. The enhanced tumor vascular permeability (VP) is the key factor responsible for this improvement. These studies were designed to identify the sequence of events leading to the improved extravasation of immunoglobulin in response to C5aAP. The VP changes were measured in mice after administration of C5aAP alongside of various mediators. The depletion of circulating polymorphonuclear neutrophils (PMN) in mice abolished the C5aAP-induced VP increase. Blocking of P-selectin also returned VP to its basal levels after the C5aAP treatment, indicating that C5aAP-induced VP changes are initiated by interactions of C5aAP with PMNs. Aminoguanidine, an inducible nitric oxide synthase (NOS) inhibitor, given before C5aAP returned VP to control levels. N(omega)-nitro-L-arginine methyl ester, a nonselective NOS inhibitor, had a marginal effect on the activity of C5aAP. Indomethacin, a nonselective cyclooxygenase inhibitor, suppressed C5aAP-induced increases in VP, whereas N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide, a selective cyclooxygenase-2 inhibitor, was active only at high doses. While C5aAP given i.p. did not alter tumor uptake of (125)I-B72.3, the i.v. administration resulted in approximately 40% increase, confirming the prerequisite interaction of C5aAP with PMNs. The sequence leading to the increased VP appears to be initiated by the interaction of C5aAP with C5a receptor expressed on PMNs followed by binding to endothelial cells of blood vessels. The interaction with P-selectin is responsible for the initiation of the nitric oxide cascade as evidenced by inducible NOS activation. Additionally, prostaglandins are required for expression of the full magnitude of the C5aAP activities.
authors.affiliation: Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198-6850, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurizaki
authors.forename: Michio
authors.initials: M
authors.lastname: Abe
authors.forename: Sam D
authors.initials: SD
authors.lastname: Sanderson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Enke
authors.forename: Janina
authors.initials: J
authors.lastname: Baranowska-Kortylewicz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D015936:Complement C5a / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006098:Granulocytes / Q000276:immunology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D019007:P-Selectin / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D009578:Nitrobenzenes; D009842:Oligopeptides; D019007:P-Selectin; D044087:Receptor, Anaphylatoxin C5a; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015936:Complement C5a; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin