Elsevier

Cancer Treatment Reviews

Volume 29, Issue 5, October 2003, Pages 371-387
Cancer Treatment Reviews

ANTI–TUMOUR TREATMENT
Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation

https://doi.org/10.1016/S0305-7372(03)00073-2Get rights and content

Abstract

Over the last decade a new cancer treatment modality, electrochemotherapy, has emerged. By using short, intense electric pulses that surpass the capacitance of the cell membrane, permeabilization can occur (electroporation). Thus, molecules that are otherwise non-permeant can gain direct access to the cytosol of cells in the treated area.

A highly toxic molecule that does not usually pass the membrane barrier is the hydrophilic drug bleomycin. Once inside the cell, bleomycin acts as an enzyme creating single- and double-strand DMA-breaks. The cytotoxicity of bleomycin can be augmented several 100-fold by electroporation. Drug delivery by electroporation has been in experimental use for cancer treatment since 1991.

This article reviews 11 studies of electrochemotherapy of malignant cutaneous or subcutaneous lesions, e.g., metastases from melanoma, breast or head- and neck cancer. These studies encompass 96 patients with altogether 411 malignant tumours. Electroporation was performed using plate or needle electrodes under local or general anaesthesia. Bleomycin was administered intratumourally or intravenously prior to delivery of electric pulses. The rates of complete response (CR) after once-only treatments were between 9 and 100% depending on the technique used. The treatment was well tolerated and could be performed on an out-patient basis.

Introduction

Electroporation has been known for about 20 years as a means to facilitate transport of normally non-permeant molecules into cells. By applying an electric field to the cells, which just surpasses the capacitance of the cell membrane, the cell membrane can be destabilized and become permeable, allowing different substances to enter the cell [1], [2].

This technique has been used in vitro to load dyes, DNA, RNA, ions, drugs and proteins into cells [3], [4], [5], [6], [7], [8]. Radiotracers, drugs and oligonucleotides have been loaded into cells in vivo [9], [10], [11], [12] and electroporation is being used as an efficient non-viral approach for gene therapy [13], [14].

As electroporation creates a direct passage through the membrane barrier, non-permeant drugs in particular gain easier access to the cytosol by electroporation (15). One such drug is the hydrophilic, charged cytotoxic agent bleomycin [6], [16]. The first use of electroporation for drug delivery in humans was for the delivery of bleomycin to skin tumours (17).

The field is now rapidly developing and several studies on the clinical use of electroporation for drug delivery to tumours are showing encouraging results.

It is now established that electrochemotherapy is an efficient, safe, inexpensive once-only treatment that can be offered to cancer patients with tumours of a variety of different histologies (T, T).

In the studies published, different approaches have been used. This review aims at: (1) describing electroporation and its use in electrochemotherapy, (2) reviewing the data published on the clinical use of electrochemotherapy using bleomycin and (3) suggesting recommendations for future use of electrochemotherapy.

Section snippets

Electroporation

When cells or tissue are exposed to direct current for a brief period of time (μs to ms) electroporation can occur. The externally applied electric field induces transmembrane potential changes that result in dielectric breakdown of the membrane once a certain threshold is surpassed [3], [15], [18]. The membrane is temporaily destabilized [1], [2] and it is generally accepted that some sort of permeation structure or “pore” is created (4). Through these permeation structures, molecules (in the

Bleomycin

Bleomycin, first discovered by Umezawa and colleagues in 1966 (58), was isolated from culture broth of the fungus Streptomyces verticillus collected from the soil at a coalmine in Japan. It is a family of at least 13 small water-soluble glycopeptidic antibiotics with a molecular weight of approximately 1500 Da [59], [60], [61]. The glycopeptides are designated A1–6, A2 and B1–6 (62). The fractions A2 and B2 make up at least 80% of the clinical mixture [61], [62]. All bleomycins contain a

Clinical trials

At the Institut Gustave-Roussy, France, the fist clinical trial of ECT with bleomycin in eight patients with recurrent or progressive head and neck squamous cell carcinoma was published in 1991 [17], [29]. Since then several clinical studies have been performed in different tumours.

Discussion

Electrochemotherapy is a novel treatment modality in cancer therapy. By performing electroporation on tumours, drug delivery can be considerably enhanced [6], [16]. Further development of the electroporation technology in the clinical setting will likely lead to delivery of DNA (13), oligonucleotides (12), and isotopes (10), so the electroporation technology may become a widespread tool in the fight against cancer. We reviewed the literature describing the clinical use of electroporation for

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