Campbell Richard A, Manyak Steven J, Yang Honghao H, Sjak-Shie Nelida N, Chen Haiming, Gui Dorina, Popoviciu Laura, Wang Cathy, Gordon Melinda, Pang Shen, Bonavida Benjamin, Said Jonathan, Berenson James R
Institute for Myeloma & Bone Cancer Research, West Hollywood, CA 90069, USA.
Int J Oncol. 2006 Jun;28(6):1409-17.
We set out to generate new human myeloma tumors that grow in immunodeficient mice and can be used for pathophysiological studies and rapid evaluation of new therapies. Fresh whole core bone marrow (BM) biopsies taken from 33 myeloma patients were engrafted into the hind limb muscle of severe combined immunodeficient (SCID) mice. Human Ig was detected in 28/33 mice and three grew palpable tumors displaying many features of human myeloma including morphology, immunophenotype and BM plasmacytosis. Following intramuscular passage, we generated large numbers of mice with predictable increases in tumor growth and human paraprotein levels. We further characterized the model generated from an IgGlambda-producing tumor known as LAGlambda-1 and determined the effects of the proteasome inhibitor bortezomib, the alkylating agent melphalan, and the DNA damaging agent liposomal doxorubicin, on the growth of this tumor. LAGlambda-1-bearing mice receiving higher doses of bortezomib showed reduced tumor growth whereas a lower dose had no effect. In contrast, melphalan did not significantly alter tumor growth, except minimally at high doses, reflecting the resistance of this patient's tumor to this drug. We also used our intramuscular (i.m.) LAGlambda-1 model to optimize the dosing schedule of liposomal doxorubicin. Low doses administered once daily three days per week decreased tumor growth and human paraprotein levels whereas much higher doses given once weekly had no anti-myeloma effects. Furthermore, LAGlambda-1 cells produce local tumors when injected subcutaneously and lytic lesions when injected intravenously allowing for multiple methods of evaluating the anti-myeloma effects of a variety of agents. Our new clinically relevant SCID models of human myeloma should greatly facilitate drug development and enable novel therapies to quickly move from the laboratory to the clinic.
我们着手培育能在免疫缺陷小鼠体内生长的新型人类骨髓瘤肿瘤，用于病理生理学研究及新疗法的快速评估。从33例骨髓瘤患者身上获取的新鲜全骨髓活检样本被植入严重联合免疫缺陷（SCID）小鼠的后肢肌肉中。在33只小鼠中有28只检测到人类免疫球蛋白，其中3只长出可触及的肿瘤，这些肿瘤表现出人类骨髓瘤的许多特征，包括形态学、免疫表型和骨髓浆细胞增多。经肌肉传代后，我们培育出大量小鼠，其肿瘤生长和人类副蛋白水平呈可预测的增加。我们进一步对由一种名为LAGlambda-1的产生IgGλ的肿瘤所构建的模型进行了表征，并确定了蛋白酶体抑制剂硼替佐米、烷化剂美法仑和DNA损伤剂脂质体阿霉素对该肿瘤生长的影响。接受高剂量硼替佐米的携带LAGlambda-1的小鼠肿瘤生长减缓，而低剂量则无效果。相比之下，美法仑除了在高剂量时有轻微影响外，并未显著改变肿瘤生长，这反映出该患者的肿瘤对这种药物具有抗性。我们还利用肌肉注射（i.m.）的LAGlambda-1模型优化脂质体阿霉素的给药方案。每周三天每天一次给予低剂量可降低肿瘤生长和人类副蛋白水平，而每周一次给予高得多的剂量则无抗骨髓瘤作用。此外，LAGlambda-1细胞皮下注射时会产生局部肿瘤，静脉注射时会产生溶解性病变，这使得能够通过多种方法评估各种药物的抗骨髓瘤效果。我们新建立的与临床相关的人类骨髓瘤SCID模型应能极大地促进药物开发，并使新疗法能够迅速从实验室进入临床。
