Mansouri A, Henle K J, Nutt A K, Nagle W A
SAAS Bull Biochem Biotechnol. 1991 Jan;4:13-6.
The development of tumor drug resistance is the major obstacle to successful systemic chemotherapy. Therefore, devising methods for reversing drug resistance is a high priority and could lead to significant improvements in cancer treatment. The mechanisms of tumor drug resistance are manifold and are not well understood. The phenomenon of multidrug resistance (MDR) represents the development of resistance to most drugs, regardless of their chemical structure. Several types of MDR are known, for example, the overexpression of a cell membrane glycoprotein (P-170), increased activity of glutathione S-transferase, elevated levels of glutathione (GSH), and alterations in topoisomerase action. A partial reversal of tumor drug resistance has been achieved by the use of competitive inhibitors for the function of glycoprotein P-170, or by the inhibition of GSH synthesis; however, this strategy has not been substantially successful for improving the response of human tumors to clinical therapy. We have recently used electroporation, in conjunction with the cytotoxic drug, cisplatin (cDDP), in an attempt to circumvent drug resistance in cDDP-resistant mouse tumor cells (RIF/Ptr1). Electroporation is the application of a high-voltage electric shock which is known to create transient pores in plasma membranes of cultured cells. Electroporation plus cDDP treatment increased intracellular cDDP concentration and reversed cellular resistance to cDDP-induced cell killing.
肿瘤耐药性的产生是全身化疗成功的主要障碍。因此，设计逆转耐药性的方法是当务之急，可能会显著改善癌症治疗效果。肿瘤耐药的机制多种多样，目前尚未完全了解。多药耐药（MDR）现象表现为对大多数药物产生耐药性，无论其化学结构如何。已知有几种类型的MDR，例如细胞膜糖蛋白（P-170）的过度表达、谷胱甘肽S-转移酶活性增加、谷胱甘肽（GSH）水平升高以及拓扑异构酶作用的改变。通过使用糖蛋白P-170功能的竞争性抑制剂或抑制GSH合成，已实现肿瘤耐药性的部分逆转；然而，该策略在改善人类肿瘤对临床治疗的反应方面尚未取得实质性成功。我们最近将电穿孔与细胞毒性药物顺铂（cDDP）联合使用，试图克服cDDP耐药小鼠肿瘤细胞（RIF/Ptr1）中的耐药性。电穿孔是施加高压电击，已知其会在培养细胞的质膜上形成瞬时孔道。电穿孔加cDDP处理增加了细胞内cDDP浓度，并逆转了细胞对cDDP诱导的细胞杀伤的耐药性。
