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

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...

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Hauptverfasser: Doleschel, Dennis (VerfasserIn) , Rix, Anne (VerfasserIn) , Arns, Susanne (VerfasserIn) , Palmowski, Karin (VerfasserIn) , Gremse, Felix (VerfasserIn) , Merkle, Ruth (VerfasserIn) , Schwörer, Florian (VerfasserIn) , Klingmüller, Ursula (VerfasserIn) , Jarsch, Michael (VerfasserIn) , Kiessling, Fabian (VerfasserIn) , Lederle, Wiltrud (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2015.05.01
In: Theranostics
Year: 2015, Jahrgang: 5, Heft: 8, Pages: 905-918
ISSN:1838-7640
DOI:10.7150/thno.11304
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.7150/thno.11304
Verlag, lizenzpflichtig, Volltext: http://www.thno.org/v05p0905.htm
Volltext
Verfasserangaben:Dennis Doleschel, Anne Rix, Susanne Arns, Karin Palmowski, Felix Gremse, Ruth Merkle, Florian Salopiata, Ursula Klingmüller, Michael Jarsch, Fabian Kiessling, Wiltrud Lederle
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 15.06.2020
Beschreibung:Online Resource
ISSN:1838-7640
DOI:10.7150/thno.11304

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