Meningeal myeloma deposits adversely impact the therapeutic index of an oncolytic VSV.
Meningeal myeloma deposits adversely impact the therapeutic index of an oncolytic VSV.
复制标题
脑膜骨髓瘤沉积物会对溶瘤 VSV 的治疗指数产生不利影响。
DOI：
10.1038/cgt.2013.63
复制
发表时间：
2013
影响因子：
6.4
通讯作者：
Russell,SJ
中科院分区：
文献类型：
--
作者：
Yarde,DN;Naik,S;Nace,RA;Peng,K-W;Federspiel,MJ;Russell,SJ
水疱性口炎病毒（VSV）在啮齿类动物中具有神经致病性，但通过将小鼠干扰素-β (IFN-β)基因植入其基因组可以将其减毒50倍。在5TGM1小鼠骨髓瘤模型中，静脉注射编码IFN-β的vsv对皮下肿瘤具有有效的活性，没有随之而来的神经毒性。然而，当静脉注射5TGM1肿瘤细胞时，经病毒处理的晚期骨髓瘤小鼠出现提示脑膜脑炎的临床体征。同时使用一种已知的活性抗骨髓瘤药物并不能延长生存期，这进一步表明死亡是由于病毒毒性，而不是肿瘤负担。组织学分析显示，系统给予5TGM1细胞种子到中枢神经系统，形成脑膜肿瘤沉积物，VSV感染并破坏这些肿瘤。死亡可能是脑膜损伤和/或病毒直接传播到邻近神经组织的结果。鉴于这些研究，在减毒vsv的临床试验中，特别是在有中枢神经系统肿瘤沉积的患者中，需要格外谨慎。
Vesicular stomatitis virus (VSV) is neuropathogenic in rodents but can be attenuated 50-fold by engineering the mouse interferon-beta (IFN-β) gene into its genome. Intravenously administered VSVs encoding IFN-β have potent activity against subcutaneous tumors in the 5TGM1 mouse myeloma model, without attendant neurotoxicity. However, when 5TGM1 tumor cells were seeded intravenously, virus-treated mice with advanced myeloma developed clinical signs suggestive of meningoencephalitis. Co-administration of a known active antimyeloma agent did not prolong survival, further suggesting that deaths were due to viral toxicity, not tumor burden. Histological analysis revealed that systemically administered 5TGM1 cells seed to the CNS, forming meningeal tumor deposits, and that VSV infects and destroys these tumors. Death is presumably a consequence of meningeal damage and/or direct transmission of virus to adjacent neural tissue. In light of these studies, extreme caution is warranted in clinical testing of attenuated VSVs, particularly in patients with CNS tumor deposits.