Abstract
Electrochemotherapy is an efficient method for the local treatment of cutaneous and subcutaneous metastases, but its efficacy as a systemic treatment remains low. The application of gene electrotransfer (GET) to transfer DNA coding for immune system modulating molecules could allow for a systemic effect, but its applications are limited because of possible side effects, e.g., immune system overactivation and autoimmune response. In this paper, we present the simultaneous electrotransfer of bleomycin and plasmid DNA as a method to increase the systemic effect of bleomycin-based electrochemotherapy. With appropriately selected concentrations of bleomycin and plasmid DNA, it is possible to achieve efficient cell transfection while killing cells via the cytotoxic effect of bleomycin at later time points. We also show the dynamics of both cell electrotransfection and cell death after the simultaneous electrotransfer of bleomycin and plasmid DNA. Therefore, this method could have applications in achieving the transient, cell death-controlled expression of immune system activating genes while retaining efficient bleomycin mediated cell killing.
Highlights
Electroporation is a widely used technique that increases the permeability of the cellular membrane by exposing the cells to electric fields of appropriate intensity and duration [1,2]
Reversible electroporation can be used in clinics to facilitate the entry of chemotherapeutic agents such as bleomycin for the local treatment of tumors (this process is known as electrochemotherapy (ECT)) [7]
As the bleomycin molecule exerts its cytotoxic effect on the cell by binding the DNA and facilitating single and double-strand cleavage [14,40], it is expected that the bleomycin molecules bind the extracellular DNA when both DNA and bleomycin are present in the extracellular medium before electroporation
Summary
Electroporation is a widely used technique that increases the permeability of the cellular membrane by exposing the cells to electric fields of appropriate intensity and duration [1,2] This technique has been positively accepted by scientific and medical communities due to its safety and effectiveness for transferring nucleic acids, drugs, etc., for pharmacological studies and clinical applications (in particular, oncological applications) [3,4]. As one of the most commonly used electro chemotherapeutic drugs, bleomycin acts as a cleaving agent for cellular DNA molecules [14], and its action results in the induction of endoplasmic stress. This may lead to the immunogenic cell death and the activation of the anti-cancer immune response [15]
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