Applying nanosecond pulse electric fields to treat skin cancer

应用纳秒脉冲电场治疗皮肤癌

• 批准号: 7917385
• 负责人: RICHARD Lee NUCCITELLI
• 金额: $ 40.94万
• 依托单位: BIOELECTROMED CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917385
• 关键词: Adverse effects; Animals; Apoptosis; Apoptotic; Basal cell carcinoma; Biological Models; Blood flow; Caliber; Caspase; Cell Death; Cell Line; Cell Nucleus; Cells; Cicatrix; Cultured Tumor Cells; Cytochromes; DNA Damage; DNA Fragmentation; Dendritic Cells; Dermatology; Disease remission; Employee Strikes; Exhibits; Fever; Figs - dietary; Frequencies; Future; Generations; Heat shock proteins; Heating; Human; Immune response; In complete remission; Inbred SENCAR Mice; Injection of therapeutic agent; Lead; Liver; Longitudinal Studies; Lung; Malignant - descriptor; Measures; Melanoma Cell; Metastatic Neoplasm to the Lung; Modeling; Mus; Necrosis; Neoplasm Metastasis; Operative Surgical Procedures; Organelles; Oxidative Stress; Pathway interactions; Patients; Physiologic pulse; Pigmentation physiologic function; Production; Protocols documentation; Quality of life; Reactive Oxygen Species; Recurrence; Reporting; Research; Role; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Squamous Cell Neoplasms; Squamous cell carcinoma; Staging; Stress; Surface; T cell response; Temperature; Time; Tissues; Treatment Protocols; Tumor Cell Nuclei; UV-induced melanoma; Work; cancer therapy; effective therapy; electric field; endonuclease; improved; melanoma; nanosecond; neoplastic cell; new technology; response; skin lesion; tumor; tumor vascular supply

DESCRIPTION (provided by applicant): We have found that extremely short electric pulses in the nanosecond range (nsPEF) can be used to treat skin cancer in mice with striking results. When 300 pulses that are 300 ns in duration and 40 kV/cm in amplitude are applied to murine melanomas, the tumors regress by 90% within two weeks. If a second such treatment is applied at that time, the tumors can be completely eliminated. A total electric field exposure time of 1.8 microseconds causes these tumors to self-destruct. The mechanism does not involve hyperthermia because we have measured the temperature within the tumor during pulse application to increase no more than 3 oC. Two targets that we have identified are the cell nucleus and the tumor's blood supply. The tumor cell nuclei shrink to half of their original size within minutes after nsPEF application and the blood flow to the tumor is halted for about two weeks. We have been conducting a long-term study of 36 mice. While none of the 18 untreated control tumors exhibited complete remission, all of the 18 nsPEF-treated tumors exhibited complete remission without recurrence for at least 120 days. The rate of metastasis of melanoma cells to lung and liver was also much lower in nsPEF-treated mice that it was in controls. Here we propose to extend this therapy to investigate the effect of nsPEF on murine squamous cell carcinoma and determine the optimal pulse parameters to completely eliminate these tumors in mouse skin. We will also determine if nsPEF treatment reduces metastasis of melanomas that are treated with nsPEF when they have grown to 8 mm in diameter. We will also determine if nsPEFs are an effective treatment of a skin tumor that has arisen from native epidermal cells. Next we will identify the mechanisms by which nsPEF triggers tumor regression. We will investigate the role of reactive oxygen species because they can generate oxidative stress-induced DNA damage. We will also investigate the involvement of the apoptosis pathway since that can also lead to DNA fragmentation. This work should determine how useful this new technology will be in future treatments of skin tumors. If this approach can be reliably used to eliminate malignant skin lesions, it could offer a welcome, scar-free alternative to surgery that could improve the quality of life for hundreds of thousands of dermatology patients yearly. This research will explore a new type of cancer therapy in which skin tumors are treated with ultra-short electric pulses. This treatment instructs the tumor to self-destruct and stops blood flow to the tumor. This promises to become a scar-free therapy that could replace surgery and improve the quality of life for hundreds of thousands of dermatology patients treated for skin cancer each year.

描述（由申请人提供）：我们发现纳秒范围内的极短电脉冲（nsPEF）可用于治疗小鼠皮肤癌，并取得惊人的效果。当对小鼠黑色素瘤施加 300 个持续时间为 300 ns、幅度为 40 kV/cm 的脉冲时，肿瘤在两周内消退了 90%。如果当时进行第二次这样的治疗，肿瘤就可以完全消除。 1.8 微秒的总电场暴露时间会导致这些肿瘤自毁。该机制不涉及高热，因为我们测量了脉冲施加期间肿瘤内的温度增加不超过 3 oC。我们已经确定的两个目标是细胞核和肿瘤的血液供应。应用 nsPEF 后几分钟内，肿瘤细胞核缩小至原始大小的一半，并且流向肿瘤的血流停止约两周。我们一直在对 36 只小鼠进行长期研究。虽然 18 个未经治疗的对照肿瘤没有一个表现出完全缓解，但所有 18 个 nsPEF 治疗的肿瘤都表现出完全缓解，并且至少 120 天没有复发。与对照组相比，接受 nsPEF 治疗的小鼠黑色素瘤细胞向肺和肝的转移率也低得多。在这里，我们建议扩展这种疗法，以研究 nsPEF 对小鼠鳞状细胞癌的影响，并确定最佳脉冲参数以完全消除小鼠皮肤中的这些肿瘤。我们还将确定当黑色素瘤直径生长至 8 毫米时，nsPEF 治疗是否会减少接受 nsPEF 治疗的黑色素瘤的转移。我们还将确定 nsPEF 是否能有效治疗由天然表皮细胞产生的皮肤肿瘤。接下来我们将确定 nsPEF 触发肿瘤消退的机制。我们将研究活性氧的作用，因为它们可以产生氧化应激诱导的 DNA 损伤。我们还将研究细胞凋亡途径的参与，因为这也会导致 DNA 断裂。这项工作应该确定这项新技术在未来皮肤肿瘤治疗中的有用性。如果这种方法能够可靠地用于消除恶性皮肤病变，它可以提供一种受欢迎的、无疤痕的手术替代方案，每年可以改善数十万皮肤病患者的生活质量。这项研究将探索一种新型癌症疗法，用超短电脉冲治疗皮肤肿瘤。这种治疗指示肿瘤自毁并阻止血液流向肿瘤。这有望成为一种无疤痕疗法，可以取代手术并改善每年数十万皮肤癌患者的生活质量。