Purpose: Bleomycin electrochemotherapy has been successfully used in preclinical studies and clinical trials for treating squamous cell carcinoma (SCC) and adenocarcinoma; however, it is not effective for treating recurrent tumors or metastatic tumors, or for preventing tumor redevelopment. In this study, we explore the coadministration of bleomycin and interleukin-12 (IL-12) followed by electroporation for treating primary and metastatic tumors. Experimental Design: Bleomycin, IL-12 plasmid DNA, or a combination of both were injected into high-grade malignant mammary tumors and SCCVII followed by electroporation. The tumor growth, survival, metastasis in lungs, CTL activity, and vascular density were analyzed.The results were analyzed by the two-sided Student's t test and Gehan's Wilcoxon test. Results: Coadministration of bleomycin and IL-12 via electroporation eradicates preestablished 4T1mammary tumors in up to 60% of mice, inhibits metastatic tumor development, and extends the long-term survival. Likewise, coadministration of bleomycin and IL-12 via electroporation eradicates squamous cell carcinoma (SCCVII) in 100% of mice and prevents tumor redevelopment in 80% of mice. Neither bleomycin nor IL-12 alone is able to achieve the same therapeutic potency. The primary role of bleomycin is to inhibit the tumor vessel development; the primary role of IL-12 is to increase the immune response that extends the survival of treated mice and inhibits the tumor redevelopment.Conclusions: This combination modality has great potential to be translated in a clinical setting for treating high-grade malignancies and for preventing tumor redevelopment.Breast cancer is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding nonmelanoma skin cancers (The American Cancer Society, 2005). According to WHO, >1.2 million people will be diagnosed with breast cancer this year worldwide. Despite the improvement in early diagnosis and treatment strategies, novel and effective alternatives for treatment, such as electrochemogenetherapy, have not been explored in breast cancer.SCC of the head and neck is the fourth most common malignancy among males. More than 40,000 cases are diagnosed per year in the United States, 60,000 in Europe, and 500,000 worldwide (1, 2). Patients with SCC of the head and neck are afflicted with a disease that profoundly influences the quality of life (3). Surgical treatment may affect essential functions, including breathing, eating, and communication.Many patients are plagued with tumor redevelopment after surgery that proves fatal. Clearly, patients need an effective but less debilitating local control treatment.Electroporation has been used extensively to deliver drugs and genes into cells. The first report of an in vivo application of electric field pulses in combination with chemotherapeutic drugs was published by Okino and Mohri (4). The process of injecting nondiffusing drugs, such as bleomycin, followed by electric pulses to transiently mak...