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Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma
Electrochemotherapy has a direct cytotoxic effect on tumour cells, and presumably, a vascular disrupting effect. In this study, on the basis of the prediction of the mathematical model, histological evaluation and physiological measurements of the tumours were carried out to confirm that electropora...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361464/ https://www.ncbi.nlm.nih.gov/pubmed/18182988 http://dx.doi.org/10.1038/sj.bjc.6604168 |
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author | Sersa, G Jarm, T Kotnik, T Coer, A Podkrajsek, M Sentjurc, M Miklavcic, D Kadivec, M Kranjc, S Secerov, A Cemazar, M |
author_facet | Sersa, G Jarm, T Kotnik, T Coer, A Podkrajsek, M Sentjurc, M Miklavcic, D Kadivec, M Kranjc, S Secerov, A Cemazar, M |
author_sort | Sersa, G |
collection | PubMed |
description | Electrochemotherapy has a direct cytotoxic effect on tumour cells, and presumably, a vascular disrupting effect. In this study, on the basis of the prediction of the mathematical model, histological evaluation and physiological measurements of the tumours were carried out to confirm that electroporation and electrochemotherapy of tumours have a vascular disrupting action. In the study, SA-1 solid subcutaneous sarcoma tumours in A/J mice were treated by bleomycin (BLM) given intravenously (1 mg kg(−1)), application of electric pulses (8 pulses, 1040 V, 100 μs, 1 Hz) or a combination of both – electrochemotherapy. The vascular effect was determined by laser Doppler flowmetry, power Doppler ultrasonographic imaging and Patent blue staining. The extent of tumour hypoxia was determined immunohistochemically by hypoxia marker pimonidazole and partial pressure of oxygen (pO(2)) in tumours by electron paramagnetic resonance oximetry. Electrochemotherapy with BLM induced good antitumour effect with 22 days, tumour growth delay and 38% tumour cures. The application of electric pulses to the tumours induced instant but transient tumour blood flow reduction (for 70%) that was recovered in 24 h. During this tumour blood flow reduction, we determined an increase in hypoxic tumour area for up to 30%, which was also reflected in reduced tumour oxygenation (for 70%). According to the described mathematical model, endothelial cells lining in tumour blood vessels are exposed to a ∼40% higher electric field than the surrounding tumour cells, and therefore easily electroporated, allowing access of high BLM concentration to the cytosol. Consequently, electrochemotherapy has, besides the immediate vascular disrupting action, also a delayed one (after 24 h), as a consequence of endothelial cell swelling and apoptosis demonstrated by extensive tumour necrosis, tumour hypoxia, prolonged reduction of tumour blood flow and significant tumour growth delay, and tumour cures. Our results demonstrate that in addition to the well-established direct cytotoxic effect on tumour cells, electrochemotherapy also has an indirect vascular disrupting action resulting altogether in extensive tumour cell necrosis leading to complete regression of tumours. |
format | Text |
id | pubmed-2361464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-23614642009-09-10 Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma Sersa, G Jarm, T Kotnik, T Coer, A Podkrajsek, M Sentjurc, M Miklavcic, D Kadivec, M Kranjc, S Secerov, A Cemazar, M Br J Cancer Translational Therapeutics Electrochemotherapy has a direct cytotoxic effect on tumour cells, and presumably, a vascular disrupting effect. In this study, on the basis of the prediction of the mathematical model, histological evaluation and physiological measurements of the tumours were carried out to confirm that electroporation and electrochemotherapy of tumours have a vascular disrupting action. In the study, SA-1 solid subcutaneous sarcoma tumours in A/J mice were treated by bleomycin (BLM) given intravenously (1 mg kg(−1)), application of electric pulses (8 pulses, 1040 V, 100 μs, 1 Hz) or a combination of both – electrochemotherapy. The vascular effect was determined by laser Doppler flowmetry, power Doppler ultrasonographic imaging and Patent blue staining. The extent of tumour hypoxia was determined immunohistochemically by hypoxia marker pimonidazole and partial pressure of oxygen (pO(2)) in tumours by electron paramagnetic resonance oximetry. Electrochemotherapy with BLM induced good antitumour effect with 22 days, tumour growth delay and 38% tumour cures. The application of electric pulses to the tumours induced instant but transient tumour blood flow reduction (for 70%) that was recovered in 24 h. During this tumour blood flow reduction, we determined an increase in hypoxic tumour area for up to 30%, which was also reflected in reduced tumour oxygenation (for 70%). According to the described mathematical model, endothelial cells lining in tumour blood vessels are exposed to a ∼40% higher electric field than the surrounding tumour cells, and therefore easily electroporated, allowing access of high BLM concentration to the cytosol. Consequently, electrochemotherapy has, besides the immediate vascular disrupting action, also a delayed one (after 24 h), as a consequence of endothelial cell swelling and apoptosis demonstrated by extensive tumour necrosis, tumour hypoxia, prolonged reduction of tumour blood flow and significant tumour growth delay, and tumour cures. Our results demonstrate that in addition to the well-established direct cytotoxic effect on tumour cells, electrochemotherapy also has an indirect vascular disrupting action resulting altogether in extensive tumour cell necrosis leading to complete regression of tumours. Nature Publishing Group 2008-01-29 2008-01-08 /pmc/articles/PMC2361464/ /pubmed/18182988 http://dx.doi.org/10.1038/sj.bjc.6604168 Text en Copyright © 2008 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Translational Therapeutics Sersa, G Jarm, T Kotnik, T Coer, A Podkrajsek, M Sentjurc, M Miklavcic, D Kadivec, M Kranjc, S Secerov, A Cemazar, M Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title | Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title_full | Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title_fullStr | Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title_full_unstemmed | Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title_short | Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
title_sort | vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361464/ https://www.ncbi.nlm.nih.gov/pubmed/18182988 http://dx.doi.org/10.1038/sj.bjc.6604168 |
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