Pajeva I K, Wiese M, Cordes H P, Seydel J K
Medicinal-Pharmaceutical Chemistry, Borstel Research Institute, Germany.
J Cancer Res Clin Oncol. 1996;122(1):27-40. doi: 10.1007/BF01203070.
The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.
双亲性药物的多药耐药性（MDR）逆转能力可能是通过它们与膜磷脂的相互作用来介导的。这可能直接（通过膜通透性和流动性的改变）和/或间接（通过抑制磷脂酰丝氨酸依赖性蛋白激酶C来抑制P-糖蛋白磷酸化，或通过周围膜双层结构组织的改变来改变膜整合蛋白的构象和功能）导致MDR的逆转。使用差示扫描量热法和核磁共振技术以及由磷脂酰胆碱或磷脂酰丝氨酸组成的人工膜，我们发现药物在阿霉素耐药的人乳腺癌MCF-7/DOX和小鼠白血病P388/DOX肿瘤细胞中的MDR逆转活性（数据取自文献）与其与磷脂酰丝氨酸相互作用的能力之间存在显著相关性。发现反式和顺式氟哌噻吨与这两种磷脂的相互作用最强，其次是三氟拉嗪、氯丙嗪、三氟丙嗪、氟桂利嗪、丙咪嗪、奎纳克林和利多卡因。反式和顺式氟哌噻吨与所研究磷脂相互作用的差异被认为是其不同MDR逆转能力的原因。维拉帕米表现出适度的膜活性，假定膜相互作用不是其高MDR逆转能力的唯一原因。胺碘酮与磷脂酰丝氨酸表现出非常强的相互作用，建议进行进一步的MDR逆转研究。
