ELECTROCHEMOTHERAPY FOR TREATING SOFT TISSUE SARCOMAS

本研究的长期目标是开发可用于增加化疗剂有效性的药物递送方法。 电脉冲与非渗透性药物如博来霉素、电化学疗法（ECT）的组合已被证明是治疗各种癌症的有效局部疗法。 ECT的成功很可能是由于药物摄取增加，这与电场的生理效应（膜通透性增加）直接相关。 因此，由于ECT在治疗其他类型的肿瘤方面显示出了希望，因此它在治疗肉瘤方面也应该有效。 重要的是建立有效的术前程序，可以最大限度地减少手术范围和不良反应。 华为有潜力填补这一角色。 这将通过完成以下具体目标来确定：i）确定ECT是否对正常组织造成任何毒性; ii）建立在大鼠模型中有效治疗肉瘤的电场强度和药物剂量的范围; iii）确定用博来霉素和电穿孔的组合治疗肉瘤的有效性;[iv）确定施加电场前后药物的具体分布]; v）确定ECT是否可用于治疗大肉瘤。将使用无胸腺大鼠模型进行工作。 将用人A-204肉瘤细胞在大鼠后肢中诱导肿瘤。 第一组实验将集中在确定药物和电场剂量的水平，这些剂量可能对正常组织，特别是肌肉，血管和神经造成毒性。 一旦电场强度和药物剂量的上限确定，工作将集中在确定ECT是否可以用于有效治疗软组织肉瘤。 这将包括建立有效剂量范围，然后在大鼠模型中治疗平均和非常大的肿瘤。 软组织肉瘤治疗中的一个重要考虑因素是能够进行保留肢体的手术，以保持功能。 ECT结合手术可以填补这一角色。

The long term goal of this research is the development of drug delivery methods that can be used to increase the effectiveness of chemotherapeutic agents. The combination of electric pulses with a nonpermeant drug such as bleomycin, electrochemotherapy (ECT), has been shown to be an effective localized therapy for the treatment of various cancers. It is quite probable that the success of ECT is due to increased drug uptake which is directly related to the physiological effects of the electric field (increased membrane permeability). Therefore, since ECT has shown promise in the treatment of other tumor types, it should also be effective in the treatment of sarcomas as well. It is important to establish effective preoperative procedures that can minimize the extent of surgery and minimize adverse effects. ECT has the potential to fill this role. This will be determined by completing the following specific aims: i) to determine if ECT causes any toxicity to normal tissue; ii) to establish the range of electrical field strength and drug dosage that is effective in treating sarcomas in a rat model; iii) to determine the effectiveness of treating sarcomas with a combination of bleomycin and electroporation; [iv) to determine the specific distribution of the drug before and after application of the electric field]; v) to determine if ECT can be used to treat large sarcomas. The work will be performed using an athymic rat model. Tumors will be induced in the hind limbs of the rat with human A-204 sarcoma cells. The first set of experiments will be focused on determining the level of drug and electric field doses that can cause toxicity to normal tissue, particularly muscle, blood vessels and nerves. Once the upper limit of electric field strength and drug dose is established the work will be focused on determining if ECT can be used to effectively treat soft tissue sarcomas. This will include establishing a range of effective dosages and then treating average and very large tumors in the rat model. An important consideration in the treatment of soft tissue sarcoma is to be able to perform limb sparing procedures which maintain functionality. ECT combined with surgery could fill this role.