Mitsiades C S, Treon S P, Mitsiades N, Shima Y, Richardson P, Schlossman R, Hideshima T, Anderson K C
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Blood. 2001 Aug 1;98(3):795-804. doi: 10.1182/blood.v98.3.795.
Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 microg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM. (Blood. 2001;98:795-804)
多发性骨髓瘤（MM）仍然无法治愈，因此迫切需要新的治疗方法。进行了临床前的体外和体内评估，以评估重组人肿瘤坏死因子（TNF）相关凋亡诱导配体/Apo2配体（TRAIL/Apo2L）在MM中的潜在治疗应用。TRAIL/Apo2L能有效诱导MM患者细胞以及大多数MM细胞系发生凋亡，包括对地塞米松（Dex）、阿霉素（Dox）、美法仑和米托蒽醌敏感或耐药的细胞。TRAIL/Apo2L还能克服白细胞介素6对MM细胞的存活作用，且不影响健康供体外周血和骨髓单个核细胞以及纯化B细胞的存活。TRAIL受体的状态（通过免疫印迹和流式细胞术评估）无法预测MM细胞对TRAIL的敏感性。在移植了人MM细胞的nu/xid/bg小鼠中证实了TRAIL/Apo2L的抗MM活性；TRAIL（每天腹腔注射500μg，共14天）耐受性良好，并显著抑制了浆细胞瘤的生长。Dox上调了TRAIL受体死亡受体5（DR5）的表达，并协同增强了TRAIL不仅针对对Dex或Dox诱导凋亡敏感的MM细胞，而且针对耐药MM细胞的作用。核因子（NF）-κB抑制剂，如SN50（一种可渗透细胞的NF-κB核转位和转录活性抑制剂）或蛋白酶体抑制剂PS-341，增强了TRAIL/Apo2L对TRAIL敏感MM细胞的促凋亡活性，而SN50逆转了ARH-77和IM-9 MM细胞对TRAIL的耐药性。重要的是，正常B淋巴细胞不会因Dox、SN50或PS-341而对TRAIL敏感。这些临床前研究表明，TRAIL/Apo2L可以克服传统耐药性，并为基于TRAIL的治疗方案的临床试验提供依据，以改善MM患者的预后。（《血液》。2001年；98:795 - 804）
