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

Doleschel D, Rix A, Arns S, Palmowski K, Gremse F, Merkle R, Salopiata F, Klingmüller U, Jarsch M, Kiessling F, Lederle W - Theranostics (2015)

Bottom Line: In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels.However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo.Doses and indications may be personalized and refined using theranostic EpoR-probes.

View Article: PubMed Central - PubMed

Affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Epo co-medication improves the accumulation of carboplatin in the tumors leading to enhanced apoptosis. A: Significantly higher platinum concentrations were measured in the Epo co-medicated (Cp + Epo) A549 (left) and H838 (right) tumors of day 21 by ICP-MS compared to the only carboplatin-treated (Cp) groups (controls: n = 5, rhuEpo-β: n = 10; *p < 0.05). B: Representative stainings (TUNEL in red, cell nuclei in blue) of whole tumor sections showing a lower degree of apoptosis in the only carboplatin-treated (Cp) compared with additionally Epo-treated tumors (Cp + Epo 5, Cp + Epo 20, scale bars: 1000 µm). C: Quantification of the TUNEL-+ area fraction demonstrates an enhanced apoptosis in additionally Epo-treated A549 (left) and H838 (right) tumors at day 21 (n = 5 per group, *p < 0.05, **p < 0.001). Cp: carboplatin, Epo 5: rhuEpo 5 µg/kg, Epo 20: rhuEpo 20 µg/kg.
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Figure 5: Epo co-medication improves the accumulation of carboplatin in the tumors leading to enhanced apoptosis. A: Significantly higher platinum concentrations were measured in the Epo co-medicated (Cp + Epo) A549 (left) and H838 (right) tumors of day 21 by ICP-MS compared to the only carboplatin-treated (Cp) groups (controls: n = 5, rhuEpo-β: n = 10; *p < 0.05). B: Representative stainings (TUNEL in red, cell nuclei in blue) of whole tumor sections showing a lower degree of apoptosis in the only carboplatin-treated (Cp) compared with additionally Epo-treated tumors (Cp + Epo 5, Cp + Epo 20, scale bars: 1000 µm). C: Quantification of the TUNEL-+ area fraction demonstrates an enhanced apoptosis in additionally Epo-treated A549 (left) and H838 (right) tumors at day 21 (n = 5 per group, *p < 0.05, **p < 0.001). Cp: carboplatin, Epo 5: rhuEpo 5 µg/kg, Epo 20: rhuEpo 20 µg/kg.

Mentions: One possible explanation for the significantly reduced tumor growth observed in the combined carboplatin- and Epo-treated tumors is an improved delivery and thus stronger accumulation of the chemotherapeutic drug due to the increased vascularization and perfusion. In order to test this hypothesis, the platinum concentration was measured in A549 and H838 tumors of day 21 by inductively coupled plasma mass spectrometry (ICP-MS). Indeed, significantly higher platinum concentrations (1.5-fold increase for A549 and 2.2-fold increase for H838) were found in Epo co-treated compared with only carboplatin-treated tumors (Fig. 5 A, A549: rhuEpo-β: 1161.25 µg/ kg ± 118.34; only carboplatin: 803.00 µg/ kg ± 210.08, *p < 0.05; H838: rhuEpo-β: 1471.75 µg/ kg ± 749.87; only carboplatin: 673.25 µg/ kg ± 274.81, *p < 0.05).


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

Doleschel D, Rix A, Arns S, Palmowski K, Gremse F, Merkle R, Salopiata F, Klingmüller U, Jarsch M, Kiessling F, Lederle W - Theranostics (2015)

Epo co-medication improves the accumulation of carboplatin in the tumors leading to enhanced apoptosis. A: Significantly higher platinum concentrations were measured in the Epo co-medicated (Cp + Epo) A549 (left) and H838 (right) tumors of day 21 by ICP-MS compared to the only carboplatin-treated (Cp) groups (controls: n = 5, rhuEpo-β: n = 10; *p < 0.05). B: Representative stainings (TUNEL in red, cell nuclei in blue) of whole tumor sections showing a lower degree of apoptosis in the only carboplatin-treated (Cp) compared with additionally Epo-treated tumors (Cp + Epo 5, Cp + Epo 20, scale bars: 1000 µm). C: Quantification of the TUNEL-+ area fraction demonstrates an enhanced apoptosis in additionally Epo-treated A549 (left) and H838 (right) tumors at day 21 (n = 5 per group, *p < 0.05, **p < 0.001). Cp: carboplatin, Epo 5: rhuEpo 5 µg/kg, Epo 20: rhuEpo 20 µg/kg.
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Related In: Results  -  Collection

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Figure 5: Epo co-medication improves the accumulation of carboplatin in the tumors leading to enhanced apoptosis. A: Significantly higher platinum concentrations were measured in the Epo co-medicated (Cp + Epo) A549 (left) and H838 (right) tumors of day 21 by ICP-MS compared to the only carboplatin-treated (Cp) groups (controls: n = 5, rhuEpo-β: n = 10; *p < 0.05). B: Representative stainings (TUNEL in red, cell nuclei in blue) of whole tumor sections showing a lower degree of apoptosis in the only carboplatin-treated (Cp) compared with additionally Epo-treated tumors (Cp + Epo 5, Cp + Epo 20, scale bars: 1000 µm). C: Quantification of the TUNEL-+ area fraction demonstrates an enhanced apoptosis in additionally Epo-treated A549 (left) and H838 (right) tumors at day 21 (n = 5 per group, *p < 0.05, **p < 0.001). Cp: carboplatin, Epo 5: rhuEpo 5 µg/kg, Epo 20: rhuEpo 20 µg/kg.
Mentions: One possible explanation for the significantly reduced tumor growth observed in the combined carboplatin- and Epo-treated tumors is an improved delivery and thus stronger accumulation of the chemotherapeutic drug due to the increased vascularization and perfusion. In order to test this hypothesis, the platinum concentration was measured in A549 and H838 tumors of day 21 by inductively coupled plasma mass spectrometry (ICP-MS). Indeed, significantly higher platinum concentrations (1.5-fold increase for A549 and 2.2-fold increase for H838) were found in Epo co-treated compared with only carboplatin-treated tumors (Fig. 5 A, A549: rhuEpo-β: 1161.25 µg/ kg ± 118.34; only carboplatin: 803.00 µg/ kg ± 210.08, *p < 0.05; H838: rhuEpo-β: 1471.75 µg/ kg ± 749.87; only carboplatin: 673.25 µg/ kg ± 274.81, *p < 0.05).

Bottom Line: In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels.However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo.Doses and indications may be personalized and refined using theranostic EpoR-probes.

View Article: PubMed Central - PubMed

Affiliation: 1. Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus