Sato W, Fukazawa N, Suzuki T, Yusa K, Tsuruo T
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Cancer Res. 1991 May 1;51(9):2420-4.
Newly synthesized quinoline derivatives were investigated for their efficacy to reverse multidrug resistance (MDR). In this study, one of the most effective quinoline derivatives, MS-073, was compared with verapamil with regard to its ability to overcome MDR in vitro and in vivo. MS-073 at 0.1 microM almost completely reversed in vitro resistance to vincristine (VCR) in VCR-resistant P388 cells. The compound also reversed in vitro VCR, adriamycin (ADM), etoposide, and actinomycin D resistance in ADM-resistant human myelogenous leukemia K562 (K562/ADM) cells, ADM-resistant human ovarian carcinoma A2780 cells, and colchicine-resistant human KB cells. MS-073 administered i.p. daily for 5 days with VCR enhanced the chemotherapeutic effect of VCR in VCR-resistant P388-bearing mice. Increases in life span of 19-50% were obtained by the combination of 100 micrograms/kg of VCR with 3-100 mg/kg of MS-073, as compared to the control. The ability of MS-073 to reverse MDR was remarkably higher, especially at low MS-073 doses, than that of verapamil, both in vitro and in vivo. MS-073 enhanced accumulation of [3H]VCR in K562/ADM cells. Photolabeling of P-glycoprotein with 200 nM [3H]azidopine in K562/ADM plasma membranes was completely inhibited by 10 microM MS-073, indicating that MS-073 reverses MDR by competitively inhibiting drug binding to P-glycoprotein.
对新合成的喹啉衍生物逆转多药耐药性（MDR）的功效进行了研究。在本研究中，就其在体外和体内克服MDR的能力而言，将最有效的喹啉衍生物之一MS-073与维拉帕米进行了比较。0.1微摩尔的MS-073几乎完全逆转了长春新碱（VCR）耐药的P388细胞对VCR的体外耐药性。该化合物还逆转了阿霉素（ADM）耐药的人髓性白血病K562（K562/ADM）细胞、ADM耐药的人卵巢癌A2780细胞和秋水仙碱耐药的人KB细胞对VCR、阿霉素、依托泊苷和放线菌素D的体外耐药性。每天腹腔注射MS-073共5天并联合VCR，可增强VCR对荷VCR耐药P388小鼠的化疗效果。与对照组相比，100微克/千克的VCR与3-100毫克/千克的MS-073联合使用可使寿命延长19%-至50%。在体外和体内，MS-073逆转MDR的能力均显著高于维拉帕米，尤其是在低MS-073剂量时。MS-073增强了[3H]VCR在K562/ADM细胞中的蓄积。10微摩尔的MS-073完全抑制了在K562/ADM质膜中用200纳摩尔[3H]叠氮平对P-糖蛋白的光标记，表明MS-073通过竞争性抑制药物与P-糖蛋白的结合来逆转MDR。
