Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus
Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus
复制标题
DOI：
10.1038/77558
复制
发表时间：
2000-07-01
期刊：
影响因子：
82.9
通讯作者：
Bell, JC
中科院分区：
文献类型：
--
作者：
Stojdl, DF;Lichty, B;Bell, JC
干扰素是与细胞表面受体结合的循环因子，激活信号级联，最终在正常细胞和肿瘤细胞中导致抗病毒反应和诱导生长抑制和/或凋亡信号(1)。利用干扰素限制患者肿瘤生长的能力的尝试结果有限(2)，因为干扰素途径中基因产物的癌症特异性突变（3-7）。尽管对干扰素无反应的癌细胞可能比正常的癌细胞获得了生长/生存优势，但它们可能同时损害了它们的抗病毒反应。为了验证这一点，我们使用了水疱性口炎病毒（VSV），这是一种包膜的负义RNA病毒(8)，对干扰素治疗非常敏感(9)。即使在完全保护正常人类原代细胞培养物的干扰素剂量存在的情况下，VSV也能在多种人类肿瘤细胞系中快速复制并选择性杀死。单次瘤内注射VSV可有效减轻裸鼠皮下移植人黑色素瘤的肿瘤负荷。我们的研究结果支持VSV作为一种具有复制能力的溶瘤病毒的使用，并展示了一种治疗干扰素无反应性肿瘤的新策略。
Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells(1). Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results(2) because of cancer-specific mutations of gene products in the interferon pathway(3-7). Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus(8) exquisitely sensitive to treatment with interferon(9) VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.