title: Radiation therapy generates platelet-activating factor agonists.
abstract: Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens.
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Sahu
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Harrison
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weyerbacher
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Joy Elizabeth
authors.initials: JE
authors.lastname: Garrett
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Helen Jan
authors.initials: HJ
authors.lastname: Chin-Sinex
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Michael Edward
authors.initials: ME
authors.lastname: Johnston
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Dynlacht
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Mendonca
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: McMullen
authors.affiliation: Department of Biostatistics, Wright State University, Dayton, OH, USA.
authors.forename: Gengxin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Dan F
authors.initials: DF
authors.lastname: Spandau
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA.|Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.|The Dayton V.A. Medical Center, Dayton, OH, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018384:Oxidative Stress; D010972:Platelet Activating Factor / Q000819:agonists*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor
keywords: antioxidants; cyclooxygenase type 2 enzyme; oxidized glycerophosphocholines; platelet-activating factor; radiation therapy