den Ouden D, van den Heuvel M, Schoester M, van Rens G, Sonneveld P
Department of Hematology, University Hospital Dijkzigt and Erasmus University, Rotterdam, The Netherlands.
Leukemia. 1996 Dec;10(12):1930-6.
Resistance to chemotherapy in multiple myeloma (MM) and acute myeloid leukemia (AML) is frequently caused by multiple drug resistance (MDR), characterized by a decreased intracellular drug accumulation. MDR is associated with expression of P-glycoprotein (P-gp). GF120918, an acridine derivative, enhances doxorubicin cell kill in resistant cell lines. In this study, the effect of GF120918 on MDR cell lines and fresh human leukemia and myeloma cells was investigated. The reduced net intracellular rhodamine-123 (Rh-123) accumulation in the MDR cell lines RPMI 8226/Dox1, /Dox4, /Dox6 and /Dox40 as compared with wild-type 8226/S was reversed by GF120918 (0.5-1.0 microM), and complete inhibition of rhodamine efflux was achieved at 1-2 microM. This effect could be maintained in drug-free medium for at least 5 h. GF120918 reversal activity was significantly reduced with a maximum of 70% in cells incubated with up to 100% serum. GF120918 significantly augmented Rh-123 accumulation in vitro in CD34-positive acute leukemia (AML) blasts and CD38-positive myeloma (MM) plasma cells obtained from 11/27 de novo AML and 2/12 refractory MM patients. A significant correlation was observed between a high P-gp expression and GF120918 induced Rh-123 reversal (P=0.0001). Using a MRK16/IgG2a ratio > or = 1.1, samples could be identified with a high probability of GF120918 reversal of Rh-123 accumulation. In conclusion, GF120918 is a promising MDR reversal agent which is active at clinically achievable serum concentrations.
多发性骨髓瘤（MM）和急性髓系白血病（AML）对化疗的耐药性通常由多药耐药（MDR）引起，其特征是细胞内药物蓄积减少。MDR与P-糖蛋白（P-gp）的表达相关。吖啶衍生物GF120918可增强耐药细胞系中阿霉素的细胞杀伤作用。在本研究中，研究了GF120918对MDR细胞系以及新鲜人白血病和骨髓瘤细胞的作用。与野生型8226/S相比，MDR细胞系RPMI 8226/Dox1、/Dox4、/Dox6和/Dox40中细胞内罗丹明-123（Rh-123）净蓄积减少，而GF120918（0.5 - 1.0微摩尔）可使其逆转，在1 - 2微摩尔时可完全抑制罗丹明外流。这种作用在无药培养基中可维持至少5小时。在高达100%血清中孵育的细胞中，GF120918的逆转活性显著降低，最大降低70%。GF120918显著增加了从11/27例初发AML和2/12例难治性MM患者获得的CD34阳性急性白血病（AML）原始细胞和CD38阳性骨髓瘤（MM）浆细胞中的Rh-123蓄积。观察到P-gp高表达与GF120918诱导的Rh-123逆转之间存在显著相关性（P = 0.0001）。使用MRK16/IgG2a比值≥1.1，可高度准确地鉴定出GF120918能逆转Rh-123蓄积的样本。总之，GF120918是一种有前景的MDR逆转剂，在临床可达到的血清浓度下具有活性。
