Antitumor effects of two newly constructed oncolytic herpes simplex viruses against renal cell carcinoma.
Antitumor effects of two newly constructed oncolytic herpes simplex viruses against renal cell carcinoma.
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DOI：
10.3892/ijo.30.6.1561
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发表时间：
2007-06
影响因子：
5.2
通讯作者：
Xinping Fu;M. Nakamori;L. Tao;R. Amato;Xiaoliu Zhang
中科院分区：
文献类型：
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作者：
Xinping Fu;M. Nakamori;L. Tao;R. Amato;Xiaoliu Zhang
条件复制（溶瘤）单纯疱疹病毒（HSV）已显示出作为治疗肾细胞癌（RCC）等实体瘤的有效药物的明显潜力。为了增强第一代 HSV 的溶瘤能力，我们最近开发了两种新的构建体。 Synco-2D 源自 HSV-1，包含两种诱导细胞膜融合的机制。 FusOn-H2 源自 HSV-2。它选择性地靶向肿瘤细胞中激活的Ras信号通路，还具有诱导细胞膜融合和细胞凋亡的能力。我们研究了 Synco-2D 和 FusOn-H2 对 RCC 的体外和体内抗肿瘤作用。 Synco-2D 和 FusOn-H2 都比 Baco-1 更容易在体外裂解人肾细胞癌细胞。对于体内研究，将溶瘤病毒通过瘤内或静脉注射给携带异种移植人肾细胞癌的裸鼠，并在治疗后监测肿瘤生长率和动物存活率。在大多数情况下，结果与第一代非融合溶瘤 HSV (Baco-1) 的结果进行比较。单次瘤内注射 Synco-2D 或 FusOn-H2 对异种移植的人肾细胞癌产生了惊人的效果，而 Baco-1 只产生中等的抗肿瘤活性。两次静脉注射 Synco-2D 也抑制了人肾细胞癌异种移植物的生长，而通过相同途径注射 Baco-1 缺乏任何可测量的抗肿瘤作用。这些数据表明，新构建的溶瘤 HSV 对动物模型中已建立的 RCC 具有有效的活性。在癌症患者中验证这些结果的临床试验似乎是有必要的。
Conditionally replicating (oncolytic) herpes simplex viruses (HSVs) have shown clear potential as effective agents for the treatment of solid tumors such as renal cell carcinoma (RCC). To enhance the oncolytic capabilities of first-generation HSVs, we recently developed two new constructs. Synco-2D is derived from HSV-1 and contains two mechanisms to induce cell membrane fusion. FusOn-H2 is derived from HSV-2. It selectively targets the activated Ras signaling pathway in tumor cells and also has the ability to induce cell membrane fusion and apoptosis. We studied the in vitro and in vivo antitumor effects of both Synco-2D and FusOn-H2 against RCC. Both Synco-2D and FusOn-H2 lysed human RCC cells in vitro much more readily than did Baco-1. For in vivo studies, the oncolytic viruses were administered either intratumorally or intravenously to nude mice bearing xenografted human RCC, and the tumor growth rate and animal survival were monitored after treatment. In most instances, the results were compared with those for a first-generation non-fusogenic oncolytic HSV (Baco-1). A single intratumoral injection of either Synco-2D or FusOn-H2 produced a striking effect against xenografted human RCC, in contrast to Baco-1, which produced only moderate antitumor activity. Two intravenous injections of Synco-2D also inhibited the growth of human RCC xenografts, while Baco-1 injections via the same route lacked any measurable antitumor effect. These data demonstrate that the newly constructed oncolytic HSVs have potent activity against established RCC in animal models. Clinical trials to validate these results in cancer patients appear warranted.