Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy

Čemažar, Maja; Parkins, C. S.; Holder, Angela; Chaplin, David J.; Tozer, Gillian M.; Serša, Gregor

doi:10.1054/bjoc.2000.1625

Cited by 85 publications

(60 citation statements)

References 19 publications

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“…The resulting antitumour effect was 9.4 days tumour growth delay, which is significantly better than the effect of single treatments, cisplatin (0.5 days tumour growth delay) and application of electric pulses (0.8 days tumour growth delay). The effect was less pronounced than in electrochemotherapy with bleomycin, which is consistent with in vitro data on endothelial cells sensitivity (Sersa et al, 1999b;Cemazar et al, 2001). The proportion of apoptotic cells increased only after electrochemotherapy with cisplatin.…”

Section: Normal Values Cisplatinsupporting

confidence: 88%

Reduced blood flow and oxygenation in SA-1 tumours after electrochemotherapy with cisplatin

et al. 2002

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Electrochemotherapy is an antitumour treatment that utilises locally delivered electric pulses to increase cytotoxicity of chemotherapeutic drugs. Besides increased drug delivery, application of electric pulses affects tumour blood flow. The aim of this study was to determine tumour blood flow modifying effects of electrochemotherapy with cisplatin, its effects on tumour oxygenation and to determine their relation to antitumour effectiveness. Electrochemotherapy of SA-1 subcutaneous tumours was performed by application of electric pulses to the tumours, following administration of cisplatin. Tumour blood flow modifying effects of electrochemotherapy were determined by measurement of tumour perfusion using the Patent blue staining technique, determination of tumour blood volume, and microvascular permeability using contrast enhanced magnetic resonance imaging, and tumour oxygenation using electron paramagnetic resonance oximetry. Antitumour effectiveness was determined by tumour growth delay and the extent of tumour necrosis and apoptosis. Tumour treatment by electrochemotherapy induced 9.4 days tumour growth delay. Tumour blood flow was reduced instantaneously and persisted for several days. This reduction in tumour blood flow was reflected in reduced tumour oxygenation. The maximal reduction in partial oxygen pressure (pO 2 ) levels was observed at 2 h after the treatment, with steady recovery to the pretreatment level within 48 h. The reduced tumour blood flow and oxygenation correlated well with the extent of tumour necrosis and tumour cells apoptosis induced by electrochemotherapy with cisplatin. Therefore, the data indicate that antitumour effectiveness of electrochemotherapy is not only due to increased cytotoxicity of cisplatin due to electroporation of tumour cells, but also due to anti-vascular effect of electrochemotherapy, which resulted in reduced tumour blood flow and oxygenation.

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Section: Normal Values Cisplatinsupporting

confidence: 88%

Reduced blood flow and oxygenation in SA-1 tumours after electrochemotherapy with cisplatin

et al. 2002

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“…This is in contrast to the significantly higher field intensities, ranging between 800 and 1,800 V/cm, previously used for electropermeabilization of endothelial cells in suspension (13) or indeed for tumor electropermeabilization in vivo (3, 10, 13). The relatively low electric fields required for electropermeabilization in our study can be explained by the shape and organization, as well as the density of endothelial cells when in a monolayer.…”

Section: Discussionmentioning

confidence: 73%

The endothelial cytoskeleton as a target of electroporation-based therapies

Kanthou

Kranjc

Serša

et al. 2006

Molecular Cancer Therapeutics

107

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Electroporation-based therapies, such as electrochemotherapy and electrogene therapy, result in the disruption of blood vessel networks in vivo and cause changes in blood flow and vascular permeability. The effects of electroporation on the cytoskeleton of cultured primary endothelial cells and on endothelial monolayer permeability were investigated to elucidate possible mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were electroporated in situ and then immunofluorescence staining for filamentous actin, B-tubulin, vimentin, and VE-cadherin as well as Western blotting analysis of levels of phosphorylated myosin light chain and cytoskeletal proteins were performed. Endothelial permeability was determined by monitoring the passage of FITC-coupled dextran through endothelial monolayers. Exposure of endothelial cells to electric pulses resulted in a profound disruption of microfilament and microtubule cytoskeletal networks, loss of contractility, and loss of vascular endothelial cadherin from cell-to-cell junctions immediately after electroporation. These effects were voltage dependent and reversible because cytoskeletal structures recovered within 60 min of electroporation with up to 40 V, without any significant loss of cell viability. The cytoskeletal effects of electroporation were paralleled by a rapid increase in endothelial monolayer permeability. These results suggest that the remodeling of the endothelial cytoskeleton and changes in endothelial barrier function could contribute to the vascular disrupting actions of electroporation-based therapies and provide an insight into putative mechanisms responsible for the observed increase in permeability and cessation of blood flow in vivo.

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“…Chemotherapy is characterized by relatively little antivascular action in vivo, which is dose-dependent. 14,15 When interpreting the fluctuations of the perfusion-associated parameters during the therapy course, hypoxia and intratumoral inflammation, especially after irradiation, play major roles. Such parameters have an impact on the perfusion-associated parameters, which cannot be predictable, as hypoxia may lead to perfusion decrease and inflammation may lead to high BV and PS values.…”

Section: Discussionmentioning

confidence: 99%

Changes in Perfusion CT of Advanced Squamous Cell Carcinoma of the Head and Neck Treated during the Course of Concomitant Chemoradiotherapy

Surlan-Popovic¹,

Bisdas²,

Rumboldt³

et al. 2009

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Concomitant chemoradiation is a promising therapy for the treatment of locoregionally advanced head and neck carcinoma. The purpose of this study was to prospectively evaluate early changes in primary tumor perfusion parameters during concomitant cisplatin-based chemoradiotherapy of locoregionally advanced SCCHN and to evaluate their predictive value for response of the primary tumor to therapy.

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Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy

Cited by 85 publications

References 19 publications

Reduced blood flow and oxygenation in SA-1 tumours after electrochemotherapy with cisplatin

Reduced blood flow and oxygenation in SA-1 tumours after electrochemotherapy with cisplatin

The endothelial cytoskeleton as a target of electroporation-based therapies

Changes in Perfusion CT of Advanced Squamous Cell Carcinoma of the Head and Neck Treated during the Course of Concomitant Chemoradiotherapy

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