Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Radiol Oncol. 2022 Mar 28;56(2):164-172. doi: 10.2478/raon-2022-0009.
One of the new treatment options for unresectable locally advanced pancreatic cancer is electrochemotherapy (ECT), a local ablative therapy that potentiates the entry of chemotherapeutic drugs into the cells, by the application of an electric field to the tumor. Its feasibility and safety were demonstrated in preclinical and clinical studies; however, there is a lack of preclinical studies assessing the actions of different drugs used in ECT, their mechanisms and interactions with other target drugs that are used in clinical practice.
The aim of the study was to determine the cytotoxicity of two chemotherapeutic drugs usually used in ECT (bleomycin and cisplatin) in the BxPC-3 human pancreatic carcinoma cell line and evaluate the interactions of ECT with the targeted drug sunitinib. First, the cytotoxicity of ECT using both chemotherapeutics was determined. In the next part, the interactions of ECT and sunitinib were evaluated through determination of combined cytotoxicity, sunitinib targets and kinetics of cell death.
The results demonstrate that ECT is effective in pancreatic cancer cell line, especially when bleomycin is used, with the onset of cell death in the first hours after the treatment, reaching a plateau at 20 hours after the treatment. Furthermore, we provide the rationale for combining ECT with bleomycin and the targeted drug sunitinib to potentiate cytotoxicity. The combined treatment of sunitinib and ECT was synergistic for bleomycin only at the highest used concentration of bleomycin 0.14 μM, whereas with lower doses of bleomycin, this effect was not observed. The interaction of ECT and treatment with sunitinib was confirmed by course of the cell death, also indicating on synergism.
ECT and sunitinib combined treatment has clinical potential, and further studies are warranted.
对于无法切除的局部晚期胰腺癌的新治疗选择之一是电化疗（ECT），这是一种局部消融疗法，通过向肿瘤施加电场来增强化疗药物进入细胞的能力。其在临床前和临床研究中已被证明具有可行性和安全性；然而，缺乏评估 ECT 中使用的不同药物的作用、其机制以及与其他在临床实践中使用的靶向药物相互作用的临床前研究。
本研究的目的是确定两种通常用于 ECT（博来霉素和顺铂）的化疗药物在 BxPC-3 人胰腺癌细胞系中的细胞毒性，并评估 ECT 与靶向药物舒尼替尼的相互作用。首先，确定了两种化疗药物的 ECT 细胞毒性。在接下来的部分中，通过测定联合细胞毒性、舒尼替尼靶点和细胞死亡动力学来评估 ECT 与舒尼替尼的相互作用。
结果表明，ECT 对胰腺癌细胞系有效，尤其是使用博来霉素时，在治疗后最初几小时内即可引起细胞死亡，在治疗后 20 小时达到高峰。此外，我们为 ECT 联合博来霉素和靶向药物舒尼替尼以增强细胞毒性提供了依据。只有在使用博来霉素的最高浓度 0.14 μM 时，舒尼替尼和 ECT 的联合治疗对博来霉素才具有协同作用，而在较低剂量的博来霉素时，这种作用并未观察到。ECT 和舒尼替尼联合治疗的相互作用通过细胞死亡的过程得到证实，也表明存在协同作用。
ECT 和舒尼替尼联合治疗具有临床潜力，需要进一步研究。
