Takeshita H, Kusuzaki K, Tsuji Y, Hirata M, Hashiguchi S, Nakamura S, Murata H, Ashihara T, Hirasawa Y
Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Japan.
Anticancer Res. 1998 Mar-Apr;18(2A):739-42.
P-glycoprotein (Pgp), a membrane drug efflux pump, is thought to be responsible for the observed drug resistance in osteosarcoma. We have recently developed Pgp-positive, multidrug resistant (MDR) murine osteosarcoma cell lines, which may be suitable models for the study of drug resistance in osteosarcoma. In this study, we investigated the effect of a newly synthesized quinoline compound, MS-209, on the reversal of doxorubicin (DOX) resistance in these cell lines. Three different types of resistance modifying agents (RMAs) as well as MS-209 were studied. These included the calcium channel blocker verapamil, and the immunosuppressive agents cyclosporin A and FK506. The reversal effects of the RMAs on DOX resistance were assessed by the MTT assay. In the absence of RMAs, the MDR osteosarcoma cells were 20-fold more resistant to DOX than the parental cells. When MS-209 was added at a final concentration of 0.1 to 3 microM to the MDR cells, 3-to 74-fold sensitization was observed. A complete reversal (37-fold sensitization) of the resistance was obtained at 1 microM MS-209. This concentration of MS-209 was 3-, 8- and 28-fold more effective than the same concentration of FK506, verapamil and cyclosporin A, respectively. These results indicate that MS-209 may be a more effective RMA, and that DOX resistance in osteosarcoma cells could be reversed by comparatively low doses of MS-209.
P-糖蛋白（Pgp）是一种膜性药物外排泵，被认为与骨肉瘤中观察到的耐药性有关。我们最近建立了Pgp阳性、多药耐药（MDR）的小鼠骨肉瘤细胞系，这些细胞系可能是研究骨肉瘤耐药性的合适模型。在本研究中，我们研究了一种新合成的喹啉化合物MS-209对这些细胞系中阿霉素（DOX）耐药性逆转的影响。研究了三种不同类型的耐药性修饰剂（RMA）以及MS-209。这些包括钙通道阻滞剂维拉帕米，以及免疫抑制剂环孢素A和FK506。通过MTT法评估RMA对DOX耐药性的逆转作用。在没有RMA的情况下，MDR骨肉瘤细胞对DOX的耐药性是亲本细胞的20倍。当以0.1至3 microM的终浓度向MDR细胞中添加MS-209时，观察到3至74倍的增敏作用。在1 microM MS-209时获得了耐药性的完全逆转（37倍增敏）。该浓度的MS-209分别比相同浓度的FK506、维拉帕米和环孢素A有效3倍、8倍和28倍。这些结果表明，MS-209可能是一种更有效的RMA，相对低剂量的MS-209可以逆转骨肉瘤细胞中的DOX耐药性。
