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: 7467197
• 负责人: RICHARD Lee NUCCITELLI
• 金额: $ 21.67万
• 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/7467197
• 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 regression; 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; Lesion; Liver; Localized; Longitudinal Studies; Lung; Malignant - descriptor; Measures; Melanoma Cell; Metastatic Neoplasm to the Lung; Modeling; Mus; Necrosis; Neoplasm Metastasis; Numbers; Operative Surgical Procedures; Organelles; Oxidative Stress; Pathway interactions; Patients; Physiologic pulse; Pigmentation physiologic function; Production; Protocols documentation; Pulse taking; Quality of life; Range; Rate; Reactive Oxygen Species; Recurrence; Reporting; Research; Role; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Squamous Cell Neoplasms; Squamous cell carcinoma; Staging; Stress; Surface; T-Lymphocyte; Temperature; Time; Tissues; Treatment Protocols; Tumor Cell Nuclei; UV-induced melanoma; Week; Work; cancer therapy; day; electric field; endonuclease; hyperthermia treatment; improved; melanoma; nanosecond; neoplastic cell; new technology; response; size; 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（NSPEF）中极短的电脉冲可用于治疗带有惊人结果的小鼠的皮肤癌。当持续时间为300 ns的300脉冲和振幅40 kV/cm的脉冲被应用于鼠黑色素瘤时，肿瘤在两周内会恢复90％。如果当时采用第二种治疗方法，则可以完全消除肿瘤。 1.8微秒的总电场暴露时间导致这些肿瘤发生自我毁灭。该机制不涉及热疗，因为我们已经测量了脉冲施用过程中肿瘤内的温度，以增加不超过3 oC。我们确定的两个靶标是细胞核和肿瘤的血液供应。肿瘤细胞核在施用NSPEF后几分钟内缩小到其原始大小的一半，并将流向肿瘤的血液停止约两个星期。我们一直对36只小鼠进行长期研究。尽管18个未经治疗的对照肿瘤中没有一个完全缓解，但所有18种NSPEF处理的肿瘤均表现出完全缓解，而无需复发至少120天。在NSPEF处理的小鼠中，黑色素瘤细胞对肺和肝脏的转移率也低得多。在这里，我们建议扩展这种疗法，以研究NSPEF对鼠鳞状细胞癌的影响，并确定最佳的脉搏参数，以完全消除小鼠皮肤中的这些肿瘤。我们还将确定NSPEF处理是否会减少黑色素瘤的转移，而黑色素瘤的直径生长到8毫米时，它们是否会减少。我们还将确定NSPEF是否是对天然表皮细胞产生的皮肤肿瘤的有效治疗方法。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。我们还将研究凋亡途径的参与，因为这也可能导致DNA碎片化。这项工作应确定这项新技术在未来对皮肤肿瘤的疗法中的用处。如果可以可靠地使用这种方法来消除恶性皮肤病变，则可以为手术提供一种受欢迎的，无疤痕的替代手术替代品，可以每年增加数十万皮肤病学患者的生活质量。这项研究将探索一种新型的癌症疗法，在其中用超短发脉冲治疗皮肤肿瘤。这种治疗方法指示肿瘤自我毁灭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接受皮肤癌治疗的数十万皮肤科患者的生活质量。