Bellamy W T, Odeleye A, Huizenga E, Dalton W S, Weinstein R S, Grogan T M
Departments of Pathology and Medicine, Arizona Cancer Center, University of Arizona, School of Medicine, Tucson, Arizona 85724, USA.
Clin Cancer Res. 1995 Dec;1(12):1563-70.
We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficiency (SCID) mouse using both the drug-sensitive 8226/S human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. As demonstrated previously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xenografts are readily detected by their immunoglobulin secretion; and (c) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output. In the current study, we have utilized this model to evaluate the in vivo efficacy of chemomodulators of P-glycoprotein-related multidrug resistance. In our initial experiments, doxorubicin alone was effective in treating the 8226/S human myeloma xenografts but had no effect on the drug-resistant 8226/C1N xenografts, in the absence of the chemosensitizing agent verapamil. In subsequent experiments, the combination of verapamil and doxorubicin resulted in both a decrease in human lambda light chain urinary excretion and an increase in survival of those animals bearing the 8226/C1N tumor. The median survival time of animals injected with 8226/C1N cells and subsequently treated with doxorubicin was 48.6 +/- 7 days, which compared to a survival of 89.6 +/- 18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001). When verapamil was added to the treatment regimen of those animals bearing the 8226/C1N xenografts, there was a 179% increase in their life span (P < 0.001), which corresponded with the observed decreased light chain in the urine. In animals receiving multiple courses of chemotherapy, an attenuated response to verapamil and doxorubicin was observed, in a manner analogous to the clinical setting of human drug-resistant myeloma escape from chemosensitivity. The SCID human myeloma xenograft model thus offers a means of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-resistant human myeloma.
我们利用药物敏感的8226/S人骨髓瘤细胞系和表达P-糖蛋白的多药耐药8226/C1N亚系，在严重联合免疫缺陷（SCID）小鼠中建立了一种可重复的人多发性骨髓瘤体内模型。如先前所示，SCID小鼠非常适合作为骨髓瘤模型，原因如下：（a）易于获得人SCID异种移植物；（b）人骨髓瘤异种移植物通过其免疫球蛋白分泌易于检测；（c）通过监测小鼠尿中人免疫球蛋白的产量，可轻易证明药物敏感与耐药细胞系中的不同治疗效果。在当前研究中，我们利用该模型评估了P-糖蛋白相关多药耐药的化学调节剂的体内疗效。在我们的初始实验中，在没有化学增敏剂维拉帕米的情况下，单独使用阿霉素对治疗8226/S人骨髓瘤异种移植物有效，但对耐药的8226/C1N异种移植物无效。在随后的实验中，维拉帕米和阿霉素联合使用导致人λ轻链尿排泄减少，并且使携带8226/C1N肿瘤的动物的生存期延长。注射8226/C1N细胞并随后用阿霉素治疗的动物的中位生存时间为48.6±7天，而接受8226/S细胞系并单独用阿霉素治疗的动物的生存期为89.6±18天（P<0.001）。当将维拉帕米添加到携带8226/C1N异种移植物的动物的治疗方案中时，它们的寿命延长了179%（P<0.001），这与观察到的尿中轻链减少相对应。在接受多疗程化疗的动物中，观察到对维拉帕米和阿霉素的反应减弱，其方式类似于人耐药骨髓瘤对化学敏感性产生逃逸的临床情况。因此，SCID人骨髓瘤异种移植模型提供了一种评估针对多药耐药人骨髓瘤中P-糖蛋白的新治疗方法的体内疗效和潜在毒性的手段。
