The clinical use of electroporation to permeabilise tumours to chemotherapy was first reported by Dr Lluis Mir and his team at the Institute Gustave Roussy, Paris in the 1990’s. Clinical experience to date is very encouraging with extensive success in the treatment of particularly difficult tumours, which have been unresponsive to chemotherapy and radiotherapy.
Electroporation involves the local delivery of brief electric pulses to tumour tissue in order to render the cell membranes more permeable. An increase in the permeability of cell membranes enables a large local absorption of a chemotherapeutic drug, which would otherwise be impermeable or poorly permeable. An increase in local absorption of the drug thus facilitates a potent localised cytotoxic effect. Although electrochemotherapy alters the membranes of tumour cells and healthy cells alike, healthy cells recover from the electric pulses and therefore absorb much less of the drug. Tumour cells which readily absorb the drug and are forced in to a cell death cascade, while leaving the vast majority of healthy cells unharmed.
Drugs used with Electroporation
Researchers in Cork Cancer Research Centre (CCRC) have found to date that Bleomycin and Cisplatin have been the most effective and suitable drugs for electrochemotherapy on gastrointestinal cancers. When cells are exposed to electric pulses, the cytotoxicity of Bleomycin increases by up to 1000 fold. These results have been observed when the drugs have been administered intravenously and intratumourally.
When Bleomycin is administered by conventional intravenous infusion, it is not particularly effective because it is a hydrophilic drug with limited transport through the cell membrane. However, when used in combination with electroporation, the effectiveness of the drug increases significantly. Once Bleomycin enters the cell it causes multiple DNA double-strand breaks, this allows the cell to survive but eliminates its ability to divide. Due to the fact that the main goal of a tumour cell is to divide, tumour cells will die off quickly as a result. The resulting cell death is largely a type of apoptotic death, where there is a minimal inflammatory reaction during involution of the tumour.
The toxicity of most other anti-cancer drugs has not been shown to be increased with electrochemotherapy as they have been designed to enter cells easily by diffusion or by drug transporters at the cell membrane. As well as this, making cells permeable is of no use for molecules that act on the cells surface. One of the major advantages to this type of treatment is the minimal dose of drug that is required. A low dose of Bleomycin can be used in electrochemotherapy in comparison to standard chemotherapy because the treatment is targeted directly to the site of the tumour, which results in a decreased risk of systemic toxicity and negative side-effects.
Clinical Success with Electroporation
This approach to cancer treatment has become quite established in the treatment of skin cancers and a lot of research has been carried out to date that has produced many published results.
Electrochemotherapy has been successfully used in the treatment of malignant melanoma, basal cell carcinoma (BCC) and skin based metastatic lesions. Electrochemotherapy has been shown to be an effective treatment in many patients and achieved an 85% positive response rate in skin cancers. The treatment typically involves a local anesthetic being injected into the cancer lesion before treatment, or less commonly a short general anesthetic may be required.
The anti-cancer drug is then either directly injected into the cancer lesion itself (intratumoural) or provided intravenously via a drip. The cancer cells are made porous by applying a very brief electrical pulse directly to the skin cancer. The electrical pulses are delivered in a fraction of a second and are very well tolerated with the appropriate anesthetic. The pulses cause only the cells directly around the electrode to become permeabilised and only these cells absorb any significant quantity of anticancer drug. The pulse generator is able to deliver pulses following the standard parameters for electroporation and delivers, measures and displays the current flowing through tissue during the treatment. The generator allows the exact calculation of the characteristics and dimensions of the electric field.
Electroporation-Benefit to Patients
The overall advantages to electrochemotherapy are that the procedure is quick and easy to perform and is more economical in relation to other standards of care. After the treatment, the patient does not require special attention and will not be required to take any post-treatment medication. The side-effects are greatly reduced due to the minimal concentration of drug that is required and the fact that healthy cells remain relatively unharmed from the procedure.
Electrochemotherapy is an efficient local treatment of tumours that has already proven its effectiveness clinically. It offers a quick, effective treatment for patients with minimal side-effects. MitaMed have developed an innovative energy-based technique called the EndoVE®, which is based on the principal of electrochemotherapy but uses an endoscopic approach. The EndoVE® is designed to be used internally for the resolution of gastrointestinal tumours.