Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype.
Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype.
复制标题
开发显示多药耐药表型的原位 SCID 小鼠-人肿瘤异种移植模型。
DOI：
10.1007/s002800050390
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发表时间：
1996
影响因子：
3
通讯作者：
Grogan,TM
中科院分区：
文献类型：
--
作者：
Bellamy,WT;Mendibles,P;Bontje,P;Thompson,F;Richter,L;Weinstein,RS;Grogan,TM
多发性骨髓瘤是一种浆细胞恶性肿瘤，尽管对化疗有很高的初始反应，但通常是无法治愈的。虽然骨髓瘤的动物模型是已知的，但人类在裸鼠和SCID小鼠身上异种移植的最新进展表明，这是一个有希望的实验模型。SCID模型尤其有希望，因为这些动物很容易接受造血和淋巴移植，通常不会发生移植物抗宿主反应。我们通过在体外逐渐增加阿霉素(ARH-D60)或米托蒽酮(ARM-80)的浓度，开发了两种人类多发性骨髓瘤细胞系ARH-77的耐药变体。当注射到受照射的SCID小鼠体内时，随着溶骨性病变的发展，ARH-D60细胞系以原位模式生长。这与8226/C1N人骨髓瘤细胞系形成对比，后者在SCID小鼠体内以播散性但非原位的方式生长。ARH-D60和ARM-80细胞株对阿霉素耐药，对米托蒽醌、长春花碱、紫杉醇和m-AMSA交叉耐药，同时保持对抗代谢物和烷化剂的敏感性。抗性亚系的生长特性和细胞周期动力学，包括S时相，没有发生改变。ARH-D60和ARM-80细胞株均表现出典型的多药耐药(MDR)表型，维拉帕米可部分逆转该表型。这两个细胞系代表了第一个多药耐药人骨髓瘤细胞系，它们在SCID小鼠体内表现出原位生长模式，因此可能对研究这种疾病的病理生理有价值。
Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. While animal models of myeloma are known, the recent developments of human xenografts in nude and SCID mice suggests a promising experimental model. The SCID model, in particular, holds promise because these animals readily accept hematopoietic and lymphoid transplantation and do not generally develop graft versus host reaction. We have developed two drug-resistant variants of the human multiple myeloma cell line ARH-77 by in vitro exposure to gradually increasing concentrations of doxorubicin (ARH-D60) or mitoxantrone (ARM-80). When injected into irradiated SCID mice, the ARH-D60 cell line grew in an orthotopic pattern with the development of osteolytic lesions. This is in contrast to the 8226/C1N human myeloma cell line which grows in a disseminated but nonorthotopic manner in the SCID mouse. Both the ARH-D60 and ARM-80 cell lines are resistant to doxorubicin and cross-resistant to mitoxantrone, vinca alkaloids, taxol and m-AMSA while maintaining sensitivity to antimetabolites and alkylating agents. Growth characteristics and cell cycle kinetics, including S-phase, were not altered in the resistant sublines. The ARH-D60 and ARM-80 cell lines both displayed a classic multidrug-resistance (MDR) phenotype which was partially reversed by the addition of verapamil. These two cell lines represent the first MDR human myeloma cell lines which have demonstrated an orthotopic growth pattern in the SCID mouse and thus may be of value in studying the pathophysiology of this disease.