Anti-tumoral effects of pulsed low electric field enhanced chemotherapy: Lessons from experimental malignant tumors

Several electric-based cancer treatments were developed to cause solid tumor ablation. These treatments are either based on electro-stimulation alone or in conjunction with chemotherapeutic drugs. Two major approaches were suggested in order to enhance the uptake of chemotherapeutic drugs by cancer cells and increase tumor destruction. The first approach, designated as electrochemotherapy (ECT) makes use of high electric fields for a short duration (electroporation). The second one, which was developed by us, was termed Low Electric Field Cancer Treatment-Enhanced Chemotherapy (LEFCT-EC), and employs a train of unipolar, pulsed low electric fields. In this chapter we summarized data on electro-stimulation treatments for cancer, and described in detail our results on the ablative effects of LEFCT-EC in various metastatic tumors in mice. In our studies we treated solid metastatic tumors with pulsed low electric fields without (LEFCT) or with chemotherapeutic agents (LEFCT-EC), and examined the efficacy of the treatments as exhibited by prolongation of survival, and cure of the tumor bearing animals. LEFCT-EC was tested against mouse metastatic tumors such as: breast carcinoma (DA3), colon carcinoma (CT-26), squamous cell carcinoma (SQ2), prostate cancer (TRAMP), and melanoma (B16F10). The treatment was applied to established subcutaneous solid lesions (5-15 mm in diameter) by percutaneously placed electrodes after local or systemic injection of various chemotherapeutic drugs such as: cisplatin, taxol, 5-fluorouracil, carmustine, doxorubicin, or bleomycin. The efficacy of LEFCT-EC was compared with the effects of chemotherapy or low electric field alone (LEFCT), and with surgery with or without chemotherapy. The results presented strongly indicate that LEFCT-EC can directly destroy the primary tumors, and facilitate the elimination of residual metastatic disease, by eliciting an anti tumoral immune response. Direct evidence for the involvement of immune defense mechanisms in eradication of metatstatic lesions, was obtained for antigenic tumors. Cured mice showed increased resistance to a tumor challenge, resistance which was abolished by treatment with an immunosuppresive drug. Further experiments revealed that inoculation of tumor cells simultaneously with splenocytes from tumor cured mice, attenuated tumor growth and prolonged the survival of inoculated animals, as compared with those which received tumor cells with splenocytes from normal mice. In the colon carcinoma model (CT-26), it was established that the protective immune cells belong to the T helper and T cytotoxic lineage. Our results indicate that LEFCT-EC is a powerful tool for tumor destruction that opens a promising approach for the treatment of human solid malignancies.