Applying nanosecond pulse electric fields to treat skin cancer

描述（由申请人提供）：我们已经发现，纳秒范围内的极短电脉冲（nsPEF）可以用于治疗小鼠的皮肤癌，具有惊人的结果。当300个脉冲的持续时间为300 ns和40 kV/cm的幅度施加到小鼠黑色素瘤，肿瘤消退90%，在两周内。如果此时进行第二次这样的治疗，肿瘤可以完全消除。1.8微秒的总电场暴露时间导致这些肿瘤自毁。该机制不涉及热疗，因为我们已经测量了在脉冲施加期间肿瘤内的温度增加不超过3 ℃。我们已经确定的两个目标是细胞核和肿瘤的血液供应。肿瘤细胞核在nsPEF应用后几分钟内缩小到其原始大小的一半，并且流向肿瘤的血流停止约两周。我们对36只小鼠进行了长期研究。虽然18个未治疗的对照肿瘤中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，至少120天没有复发。在nsPEF处理的小鼠中，黑色素瘤细胞向肺和肝的转移率也远低于对照组。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，并确定最佳的脉冲参数，以完全消除小鼠皮肤中的这些肿瘤。我们还将确定nsPEF治疗是否减少了用nsPEF治疗的黑色素瘤在直径生长至8 mm时的转移。我们还将确定nsPEFs是否是由天然表皮细胞引起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。我们还将研究细胞凋亡途径的参与，因为这也可能导致DNA片段化。这项工作应该确定这项新技术在未来皮肤肿瘤治疗中的用途。如果这种方法可以可靠地用于消除恶性皮肤病变，它可以提供一个受欢迎的，无疤痕的替代手术，可以提高生活质量的数十万皮肤病患者每年。这项研究将探索一种新型的癌症治疗方法，其中皮肤肿瘤用超短电脉冲治疗。这种治疗指导肿瘤自毁并阻止血液流向肿瘤。这有望成为一种无疤痕的治疗方法，可以取代手术，并改善每年数十万皮肤癌患者的生活质量。

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.