Neuroscience Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Cancer Gene Ther. 2010 Apr;17(4):266-74. doi: 10.1038/cgt.2009.71. Epub 2009 Oct 16.
Schwannomas are benign tumors forming along peripheral nerves that can cause deafness, pain and paralysis. Current treatment involves surgical resection, which can damage associated nerves. To achieve tumor regression without damage to nerve fibers, we generated an HSV amplicon vector in which the apoptosis-inducing enzyme, caspase-1 (ICE), was placed under the Schwann cell-specific P0 promoter. Infection of schwannoma, neuroblastoma and fibroblastic cells in culture with ICE under the P0 promoter showed selective toxicity to schwannoma cells, while ICE under a constitutive promoter was toxic to all cell types. After direct intratumoral injection of the P0-ICE amplicon vector, we achieved marked regression of schwannoma tumors in an experimental xenograft mouse model. Injection of this amplicon vector into the sciatic nerve produced no apparent injury to the associated dorsal root ganglia neurons or myelinated nerve fibers. The P0-ICE amplicon vector provides a potential means of 'knifeless resection' of schwannoma tumors by injection of the vector into the tumor with low risk of damage to associated nerve fibers.
施万细胞瘤是沿着外周神经形成的良性肿瘤，可导致耳聋、疼痛和瘫痪。目前的治疗方法包括手术切除，这可能会损伤相关的神经。为了在不损伤神经纤维的情况下实现肿瘤消退，我们生成了一种 HSV 扩增子载体，其中凋亡诱导酶 caspase-1（ICE）置于 Schwann 细胞特异性 P0 启动子下。在 P0 启动子下，用 ICE 感染培养的施万细胞瘤、神经母细胞瘤和成纤维细胞显示出对施万细胞瘤的选择性毒性，而组成型启动子下的 ICE 对所有细胞类型都有毒性。在实验性异种移植小鼠模型中，直接瘤内注射 P0-ICE 扩增子载体后，我们实现了施万细胞瘤的显著消退。将这种扩增子载体注入坐骨神经，对相关的背根神经节神经元或有髓神经纤维没有明显的损伤。P0-ICE 扩增子载体通过将载体注入肿瘤中，为施万细胞瘤的“无刀切除”提供了一种潜在的手段，同时降低了损伤相关神经纤维的风险。
