Dalton W S, Durie B G, Alberts D S, Gerlach J H, Cress A E
Cancer Res. 1986 Oct;46(10):5125-30.
Multiple myeloma is a disease with a high initial chemotherapeutic response but virtually no cures due to emergence of drug resistance. A doxorubicin-resistant human myeloma cell line (8226/Dox) has been selected from the myeloma cell line RPMI8226 by continuously exposing cells to gradually increasing doses of doxorubicin. The resistant phenotype has been retained for over 2 months despite growth in drug-free medium. The resistant subline was cross-resistant to mitoxantrone, acronycine, etoposide, and vincristine. The 8226/Dox cell line remained sensitive to melphalan but acquired collateral sensitivity to dexamethasone. Intracellular doxorubicin accumulation, as measured by [14C]doxorubicin and high-performance liquid chromatography, was decreased by 54% at 1 h for 8226/Dox compared to the sensitive line. Efflux of doxorubicin was significantly greater in the resistant subline as compared to the sensitive parent cell line. Membrane analysis using immunoblotting techniques detected increased expression of the integral membrane protein P-glycoprotein (Mr 170,000) in the resistant subline. Cytogenetic analysis of 8226/Dox revealed a 7q-anomaly not seen in the parent cell line. No double minutes or homogeneously staining regions were observed. The drug sensitivity/resistance pattern of the resistant cell line correlates well with clinical observations indicating the potential of this cell line as a model for resistance in multiple myeloma.
多发性骨髓瘤是一种初始化疗反应率较高但因耐药性出现而几乎无法治愈的疾病。通过将细胞持续暴露于逐渐增加剂量的阿霉素中，从骨髓瘤细胞系RPMI8226中筛选出了一种阿霉素耐药的人骨髓瘤细胞系（8226/Dox）。尽管在无药物培养基中生长，但耐药表型已保留了两个多月。该耐药亚系对米托蒽醌、吖啶酮、依托泊苷和长春新碱具有交叉耐药性。8226/Dox细胞系对美法仑仍敏感，但对地塞米松获得了协同敏感性。通过[14C]阿霉素和高效液相色谱法测定，与敏感细胞系相比，8226/Dox在1小时时细胞内阿霉素积累量减少了54%。与敏感亲代细胞系相比，耐药亚系中阿霉素的外排明显更高。使用免疫印迹技术进行的膜分析检测到耐药亚系中整合膜蛋白P-糖蛋白（分子量170,000）的表达增加。对8226/Dox的细胞遗传学分析显示出亲代细胞系中未出现的7号染色体长臂异常。未观察到双微体或均匀染色区。耐药细胞系的药物敏感性/耐药模式与临床观察结果密切相关，表明该细胞系作为多发性骨髓瘤耐药模型的潜力。
