Goel Apollina, Carlson Stephanie K, Classic Kelly L, Greiner Suzanne, Naik Shruthi, Power Anthony T, Bell John C, Russell Stephen J
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Blood. 2007 Oct 1;110(7):2342-50. doi: 10.1182/blood-2007-01-065573. Epub 2007 May 21.
Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Delta51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Delta51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Delta51)-NIS-infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Delta51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of (123)I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Delta51)-NIS plus (131)I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Delta51)-NIS was combined with (131)I. These results show that VSV(Delta51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.
多发性骨髓瘤是一种对放疗敏感但目前无法治愈的恶性肿瘤。在此，我们构建了一种新型重组水泡性口炎病毒[VSV(Delta51)-NIS]，其基质蛋白中的甲硫氨酸51缺失，并表达人钠碘同向转运体（NIS）基因。VSV(Delta51)-NIS对骨髓瘤细胞系和原代骨髓瘤细胞表现出特异性溶瘤活性，且能够在体外骨髓瘤细胞中复制至高滴度。碘摄取试验显示，放射性碘在VSV(Delta51)-NIS感染的骨髓瘤细胞中积累，这是NIS转基因功能所特有的。在已建立皮下骨髓瘤肿瘤的bg/nd/xid小鼠中，给予VSV(Delta51)-NIS导致肿瘤内病毒大量复制和肿瘤消退。未观察到与VSV相关的神经毒性。通过对(123)I-碘生物分布进行连续γ相机成像，以非侵入性方式监测感染在肿瘤内的扩散。基于这些图像的剂量学计算表明，VSV(Delta51)-NIS联合(131)I进行放射性病毒联合治疗具有可行性。患有同基因5TGM1骨髓瘤肿瘤（皮下或原位）的免疫活性小鼠，当VSV(Delta51)-NIS与(131)I联合使用时，肿瘤消退和生存期均有显著改善。这些结果表明，VSV(Delta51)-NIS是一种安全的溶瘤剂，在多发性骨髓瘤中具有显著的治疗潜力。
