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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.
AuthorsDennis Doleschel, Anne Rix, Susanne Arns, Karin Palmowski, Felix Gremse, Ruth Merkle, Florian Salopiata, Ursula Klingmüller, Michael Jarsch, Fabian Kiessling, Wiltrud Lederle
JournalTheranostics (Theranostics) Vol. 5 Issue 8 Pg. 905-18 ( 2015) ISSN: 1838-7640 [Electronic] Australia
PMID26000061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Therapeutic Uses
  • Erythropoietin
  • Carboplatin
Topics
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology)
  • Carboplatin (pharmacokinetics, pharmacology)
  • Carcinoma, Non-Small-Cell Lung (drug therapy)
  • Cell Line, Tumor
  • Disease Models, Animal
  • Erythropoietin (administration & dosage)
  • Female
  • Heterografts
  • Humans
  • Mice, Nude
  • Neovascularization, Pathologic
  • Perfusion
  • Therapeutic Uses

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