Erythropoietin improves the accumulation and therapeutic effects of carboplatin by enhancing tumor vascularization and perfusion

• Verfasst von: Doleschel, Dennis [VerfasserIn]
• Verfasst von: Rix, Anne [VerfasserIn]
• Verfasst von: Arns, Susanne [VerfasserIn]
• Verfasst von: Palmowski, Karin [VerfasserIn]
• Verfasst von: Gremse, Felix [VerfasserIn]
• Verfasst von: Merkle, Ruth [VerfasserIn]
• Verfasst von: Salopiata, Florian [VerfasserIn]
• Verfasst von: Klingmüller, Ursula [VerfasserIn]
• Verfasst von: Jarsch, Michael [VerfasserIn]
• Verfasst von: Kiessling, Fabian [VerfasserIn]
• Verfasst von: Lederle, Wiltrud [VerfasserIn]
• Titel: Erythropoietin improves the accumulation and therapeutic effects of carboplatin by enhancing tumor vascularization and perfusion
• Verf.angabe: Dennis Doleschel, Anne Rix, Susanne Arns, Karin Palmowski, Felix Gremse, Ruth Merkle, Florian Salopiata, Ursula Klingmüller, Michael Jarsch, Fabian Kiessling, Wiltrud Lederle
• E-Jahr: 2015
• Jahr: 2015.05.01
• Umfang: 14 S.
• Fussnoten: Gesehen am 15.06.2020
• Titel Quelle: Enthalten in: Theranostics
• Ort Quelle: Wyoming, NSW : Ivyspring, 2011
• Jahr Quelle: 2015
• Band/Heft Quelle: 5(2015), 8, Seite 905-918
• ISSN Quelle: 1838-7640
• DOI: doi:10.7150/thno.11304
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1700575414

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.