Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: Virus persists and spreads systemically at late time points
Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: Virus persists and spreads systemically at late time points
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DOI：
10.1089/104303403321467199
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发表时间：
2003-03-01
影响因子：
4.2
通讯作者：
Hay, JG
中科院分区：
文献类型：
--
作者：
Sauthoff, H;Hu, J;Hay, JG
溶瘤复制型腺病毒是一种有前途的治疗癌症的新模式。尽管假定病毒持续复制并从感染的癌细胞传播到未感染的癌细胞具有生物学优势，但早期临床试验表明，目前载体的功效有限。在使用免疫缺陷小鼠的异种移植肿瘤模型中，野生型腺病毒也很少能够根除已建立的肿瘤。这表明先天免疫机制可以清除病毒，或者肿瘤内的屏障可以阻止病毒传播。本研究的目的是评价在人肿瘤异种移植模型中瘤内注射病毒后病毒分布和扩散的动力学。瘤内注射野生型病毒后，高水平的可滴定病毒在异种移植肿瘤内持续至少8周。通过免疫组织化学确定的肿瘤内的病毒分布是斑片状的，并且病毒感染的细胞似乎两侧是肿瘤坏死和结缔组织。病毒感染的细胞的肿瘤支持结构，这是鼠源的紧密接近，清楚地证明了使用DNA探针，特异性杂交的B1小鼠DNA重复。重要的是，尽管在瘤内注射后6小时病毒从循环中清除，但在4周后检测到病毒的全身传播。此外，受感染肿瘤的血管被坏死和病毒感染肿瘤细胞的前进边缘包围，表明异种移植肿瘤通过血管系统再感染。这些数据表明，人腺病毒在肿瘤异种移植物内的传播受到鼠肿瘤支持结构的损害。此外，有证据表明病毒在肿瘤内持续复制，随后通过肿瘤血管系统全身传播和肿瘤再感染。尽管免疫缺陷模型存在局限性，但了解病毒与荷瘤宿主之间的相互作用对于设计有效的治疗方法非常重要。
Oncolytic replicating adenoviruses are a promising new modality for the treatment of cancer. Despite the assumed biologic advantage of continued viral replication and spread from infected to uninfected cancer cells, early clinical trials demonstrate that the efficacy of current vectors is limited. In xenograft tumor models using immune-incompetent mice, wild-type adenovirus is also rarely able to eradicate established tumors. This suggests that innate immune mechanisms may clear the virus or that barriers within the tumor prevent viral spread. The aim of this study was to evaluate the kinetics of viral distribution and spread after intratumoral injection of virus in a human tumor xenograft model. After intratumoral injection of wild-type virus, high levels of titratable virus persisted within the xenograft tumors for at least 8 weeks. Virus distribution within the tumors as determined by immunohistochemistry was patchy, and virus-infected cells appeared to be flanked by tumor necrosis and connective tissue. The close proximity of virus-infected cells to the tumor-supporting structure, which is of murine origin, was clearly demonstrated using a DNA probe that specifically hybridizes to the B1 murine DNA repeat. Importantly, although virus was cleared from the circulation 6 hr after intratumoral injection, after 4 weeks systemic spread of virus was detected. In addition, vessels of infected tumors were surrounded by necrosis and an advancing rim of virus-infected tumor cells, suggesting reinfection of the xenograft tumor through the vasculature. These data suggest that human adenoviral spread within tumor xenografts is impaired by murine tumor-supporting structures. In addition, there is evidence for continued viral replication within the tumor, with subsequent systemic dissemination and reinfection of tumors via the tumor vasculature. Despite the limitations of immune-incompetent models, an understanding of the interactions between the virus and the tumor-bearing host is important in the design of effective therapies.