ELECTROCHEMOTHERAPY FOR TREATING SOFT TISSUE SARCOMAS

这项研究的长期目标是开发可用于提高化疗药物有效性的药物输送方法。电脉冲与博莱霉素、电化疗(ECT)等非手段药物的结合已被证明是治疗各种癌症的一种有效的局部疗法。ECT的成功很可能是由于药物摄取的增加，而药物摄取与电场的生理效应(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，它在肉瘤的治疗中也应该是有效的。重要的是建立有效的术前程序，将手术范围降至最低，并将不良反应降至最低。ECT有潜力填补这一角色。为此，将通过完成下列特定目标来确定：i)确定ECT是否对正常组织造成任何毒性；ii)确定用于治疗大鼠肉瘤的有效电场强度和药物剂量范围；iii)确定博莱霉素和电穿孔联合治疗肉瘤的有效性；[iv)确定药物在施加电场前后的具体分布]；v)确定ECT是否可用于治疗大型肉瘤。这项工作将使用无菌大鼠模型进行。用人A-204肉瘤细胞在大鼠后肢诱发肿瘤。第一组实验将集中在确定药物和电场剂量的水平，这些剂量可能会对正常组织造成毒性，特别是肌肉、血管和神经。一旦确定了电场强度和药物剂量的上限，这项工作将集中在确定ECT是否可以有效地治疗软组织肉瘤。这将包括建立一个有效剂量范围，然后治疗大鼠模型中的平均和非常大的肿瘤。在软组织肉瘤的治疗中，一个重要的考虑因素是能够进行保持功能的保肢手术。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.