title: Erythropoietin improves the accumulation and therapeutic effects of carboplatin by enhancing tumor vascularization and perfusion.
abstract: Recombinant human erythropoietin (rhuEpo) is currently under debate for the treatment of chemotherapy-induced anemia due to clinical trials showing adverse effects in Epo-treated patients and the discovery of the erythropoietin-receptor (EpoR) in tumor and endothelial cells. Here, using Epo-Cy5.5 as theranostic near-infrared fluorescent probe we analyzed the effects of rhuEpo as co-medication to carboplatin in non-small-cell-lung-cancer (NSCLC)-xenografts with different tumor cell EpoR-expression (H838 ~8-fold higher than A549). Nude mice bearing subcutaneous A549 and H838 NSCLC-xenografts received either only carboplatin or carboplatin and co-medication of rhuEpo in two different doses. Tumor sizes and relative blood volumes (rBV) were longitudinally measured by 3D-contrast-enhanced ultrasound (3D-US). Tumoral EpoR-levels were determined by combined fluorescence molecular tomography (FMT)/ micro computed tomography (µCT) hybrid imaging. We found that rhuEpo predominantly acted on the tumor endothelium. In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels. Accordingly, rhuEpo induced EpoR-phoshorylation and stimulated proliferation of endothelial cells. However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo. This is explained by the Epo-mediated vascular remodeling leading to improved drug delivery as obvious by a more than 2-fold higher carboplatin accumulation and significantly enhanced tumor apoptosis. In addition, co-medication of rhuEpo reduced tumor hypoxia and diminished intratumoral EpoR-levels which continuously increased during carboplatin (Cp) -treatment. These findings suggest that co-medication of rhuEpo in well balanced doses can be used to improve the accumulation of anticancer drugs. Doses and indications may be personalized and refined using theranostic EpoR-probes.
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Doleschel
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Rix
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Arns
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany. ; 2. Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Palmowski
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gremse
authors.affiliation: 3. Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Merkle
authors.affiliation: 3. Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. ; 4. Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Salopiata
authors.affiliation: 3. Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. ; 4. Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.affiliation: 5. Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Penzberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Jarsch
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Lederle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016190:Carboplatin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010477:Perfusion; D045506:Therapeutic Uses
chemical_list: D000970:Antineoplastic Agents; D045506:Therapeutic Uses; D004921:Erythropoietin; D016190:Carboplatin
keywords: Angiogenesis; Chemotherapy; Fluorescence Molecular Tomography; Lung cancer; Non-Invasive Imaging; Theranostic Agent