Cytotoxic agents for electrochemotherapy: Efficacy, mechanisms of action, potential candidates

Electrochemotherapy (ECT) is a popular clinical anticancer treatment modality that combines chemotherapy with electroporation to enhance drug uptake by tumor cells. One of its key advantages is the ability to use significantly reduced drug concentrations, thereby, minimizing cytotoxic effects on healthy cells and thus, side-effects of the therapy when compared to conventional chemotherapy. The therapeutic efficacy of ECT depends upon two main components: pulsed electric field (PEF) parameters and physiochemical properties of anticancer agents, including their molecular structure, mechanism of action, and tumor specificity. This review provides the comprehensive survey of cytotoxic compounds that are either currently used or are under investigation for ECT-compatibility. Bleomycin and cisplatin are most established drugs in this context, however, other compound such as mitomycin C, doxorubicin, or calcium have showed encouraging outcomes in preclinical and clinical studies. We have further analyzed the cytotoxic profiles, mechanisms of action, and therapeutic outcomes of various agents, compatibility with pulsed electric field protocols based on data of clinical trials, in vivo and in vitro models. Furthermore, we discuss and summarize other potential cytotoxic agent candidates, which have not been yet tested in ECT context, which include chemotherapeutics and natural compounds categorized by their cytotoxic potential and synergy with electroporation.