Preclinical Validation of Electrochemotherapy as an Effective Treatment for Brain Tumors

Abstract

Electrochemotherapy represents a strategy to enhance chemotherapeutic drug uptake by delivering electrical pulses which exceed the dielectric strength of the cell membrane, causing transient formation of structures that enhance permeabilization. Here we show that brain tumors in a rat model can be eliminated by electrochemotherapy with a novel electrode device developed for use in the brain. By using this method, the cytotoxicity of bleomycin can be augmented more than 300-fold because of increased permeabilization and more direct passage of drug to the cytosol, enabling highly efficient local tumor treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment, we found that 9 of 13 rats (69%) receiving electrochemotherapy displayed a complete elimination of tumor, in contrast to control rats treated with bleomycin only, pulses only, or untreated where tumor progression occurred in each case. Necrosis induced by electrochemotherapy was restricted to the treated area, which MRI and histology showed to contain a fluid-filled cavity. In a long-range survival study, treatment side effects seemed to be minimal, with normal rat behavior observed after electrochemotherapy. Our findings suggest that electrochemotherapy may offer a safe and effective new tool to treat primary brain tumors and brain metastases. Cancer Res; 71(11); 3753-62. Ó2011 AACR.

Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis

“…Systemic administration of calcium was not tested in this study, as adsorption to plasma proteins and risk of hypercalcemia were predicted. Because electrochemotherapy has proved efficient in cutaneous tumors, electrodes facilitating the application of electroporation for use in colorectal cancer, bone and liver metastases, and brain tumors (19) have been developed, and are now in clinical trials (7). Efforts are also being made to carry out irreversible electroporation of tumors (7) in which addition of calcium could enhance efficacy.…”

In Vitro and In Vivo Experiments on Electrochemotherapy for Bladder Cancer

“…6e8 A single case report describes a CR in a patient with cutaneous metastasis of transitional cell carcinoma. 6 However, to our knowledge electrochemotherapy for bladder cancer has not been investigated to date.…”

Photochemical internalization of bleomycin for glioma treatment

“…Electrochemotherapy with BLM on tumor-bearing rats has been done and demonstrated increased survival time compared to that of untreated animals. 30,31 In these experiments, BLM was injected intracranially, and the effects of electroporation were very pronounced both on the tumor and on the normal brain. 31 Although these preclinical results were encouraging, the application of electrochemotherapy to the clinical situation for the postoperative treatment of glioma patients would be extremely problematic.…”

“…30,31 In these experiments, BLM was injected intracranially, and the effects of electroporation were very pronounced both on the tumor and on the normal brain. 31 Although these preclinical results were encouraging, the application of electrochemotherapy to the clinical situation for the postoperative treatment of glioma patients would be extremely problematic. On the other hand, PCI-mediated drug delivery, which duplicates many of the effects of electroporation, is translatable into clinical protocols through the use of balloon catheter radiation or light applicators implanted into the resection cavity following tumor resection.…”