Wang Hua, Xiao Lifeng, Tao Jianguo, Srinivasan Venkat, Boyce Brendan F, Ebetino Frank H, Oyajobi Babatunde O, Boeckman Robert K, Xing Lianping
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA.
Institute of Stomatology, Nanjing Medical University, Jiangsu Key Laboratory of Oral Diseases, Nanjing 210029, China.
Pharmaceutics. 2018 Sep 10;10(3):154. doi: 10.3390/pharmaceutics10030154.
Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM.
多发性骨髓瘤（MM）是影响骨骼和骨髓的最常见癌症，大多数患者仍无法治愈；因此需要新的治疗方法。硼替佐米（Btz）是一种经美国食品药品监督管理局（FDA）批准用于治疗MM患者的药物。然而，其严重的副作用需要降低剂量或可能停止治疗。为克服这一局限性，我们使用一种新型化学连接体将Btz与缺乏抗破骨细胞活性的双膦酸盐（BP）残基偶联，生成了一种新的基于Btz的骨靶向（BP-Btz）蛋白酶体抑制剂。我们证明，BP-Btz而非Btz与骨切片结合，并在体外抑制MM细胞的生长。在MM小鼠模型中，与Btz相比，BP-Btz更有效地减轻了肿瘤负担和骨质流失，且全身副作用更小。因此，BP-Btz可能代表一种治疗MM患者的新方法。
