Increased platinum accumulation in SA-1 tumour cells after in vivo electrochemotherapy with cisplatin

Abstract

Summary Electrochemotherapy is an anti-tumour treatment that utilizes locally delivered electric pulses to increase cytotoxicity of chemotherapeutic drugs. The aim of our study was to determine whether anti-tumour effectiveness of electrochemotherapy with cisplatin is a consequence of increased plasma membrane permeability caused by electroporation that enables cisplatin binding to DNA. For this purpose, anti-tumour effectiveness of electrochemotherapy was evaluated on SA-1 tumours treated with electric pulses 3 min after intravenous injection of cisplatin (4 mg kg -1 ). Anti-tumour effectiveness was correlated with platinum accumulation in tumours and the amount of platinum bound to DNA, as determined by atomic absorption spectrometry. In tumours treated with electrochemotherapy, cell kill was increased by a factor of 20 compared with treatment with cisplatin only, as determined from tumour growth curves. The amount of platinum bound to DNA and platinum content in the tumours treated by electrochemotherapy was approximately two times higher than in cisplatin-treated tumours. Based on our results, we conclude that in vivo application of electric pulses potentiates anti-tumour effectiveness of cisplatin by electroporation that consequently results in cisplatin increased delivery into the cells. In addition, besides electroporation, immune system and tumour blood flow changes could be involved in the observed anti-tumour effectiveness of electrochemotherapy.

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

“…It is therefore probable that in vivo electrochemotherapy, especially with bleomycin, may directly damage the vascular endothelium and account for its antivascular actions, such as reduced tumour blood flow and infiltration by host blood cells (Sersa et al, 1999a, b). The antivascular action of electrochemotherapy would be in addition to other, non-vascular, mechanisms previously reported (Sersa et al, 1997a, b;Cemazar et al, 1999). Continuous exposure of human endothelial cells to bleomycin or cisplatin reduced cell survival substantially in a dose-dependent manner although this effect was more pronounced with bleomycin than with cisplatin.…”

“…In the present study, electric pulses were used as a drug delivery system for bleomycin and cisplatin, which both are reported to have restricted transport through plasma membrane (Belehradek et al, 1994;Cemazar et al, 1999). Increased drug uptake and potentiation of cytotoxicity has been demonstrated in vitro for several tumour cell lines treated with cisplatin, bleomycin, peplomycin and others, following exposure to electric pulses (Orlowski et al, 1988;Sersa et al, 1995;Kambe et al, 1996;Cemazar et al, 1998a;Kuriyama et al, 1999).…”

“…accumulation has been confirmed for platinum (component of cisplatin) and radioactively labelled bleomycin into tumour cells in vivo after treatment with electrochemotherapy (Belehradek et al, 1994;Cemazar et al, 1999). However, several other mechanisms have been demonstrated to be involved in tumour response to electrochemotherapy, e.g.…”

“…We have previously shown that the application of electric pulses alone result in substantial, but transient, reduction of tumour perfusion (Sersa et al, 1999a) and furthermore that electrochemotherapy with bleomycin causes rapid cessation of tumour perfusion (Sersa et al, 1999b). In addition, electrochemotherapy prolonged entrapment of cisplatin for up to 8 hours within the tumour (Cemazar et al, 1999). We hypothesize that the anti-tumour action of electrochemotherapy may be partly due to its antivascular action.…”

Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma

“…of at least three mice per point. also leading to an approximately twofold increase of binding of cisplatin to DNA (Belehradek et al, 1994;Cemazar et al, 1999). This enables increased cytotoxicity of the drugs such as BLM or cisplatin, particularly in the cells that are exposed to electric fields that cause their electroporation.…”