OBJECTIVE The exposure of cells in vitro to trains of low voltage-pulsed electric fields in the range of 20-100 V/cm was previously shown to induce an efficient uptake of macromolecules with molecular weight in the range of M(r) 300-2,000,000 via an endocytic-like process. This study examines the antitumor effectiveness of treatment based on similar exposure of solid tumors in mice to low electric fields (LEFs) in the presence of chemotherapeutic agents. METHODS LEF was applied to approximately 5 mm in diameter (60-70 mm(3)) s.c. B16-F10.9 melanoma tumors by percutaneously placed electrodes after intratumoral injection of either cis-platinum(II) diamminedichloride, Taxol, 5-fluorouracil, or bleomycin. RESULTS Significant eradication of primary tumors, prolongation of survival, and complete cure of some of the C57Bl/6 mice from both primary tumors and metastases were achieved using this technique with cis-platinum(II) diamminedichloride, bleomycin, and Taxol (13.5, 8, and 26% cure rate, respectively). Mice cured by LEF-enhanced chemotherapy and challenged with a tumorigenic dose of B16-F10.9 cells lived significantly longer than first time inoculated ones, and 23.5% of the challenged mice did not develop tumors at all. Spleen cells from the cured mice that were inoculated together with B16-F10.9 cells inhibited the primary tumor growth in intact mice. Histological analysis of tumor sections of LEF-enhanced chemotherapy-treated mice revealed multiple necrotic areas, apoptosis, and massive infiltrates of T lymphocytes and macrophages. Low voltage electrochemotherapy with Taxol was shown to be more effective than surgical removal of the tumor with Taxol. CONCLUSIONS These findings indicate that LEF-enhanced chemotherapy is an effective treatment of animals bearing metastatic melanoma.