Development of molecular therapy targeted for tumor cell and tumor stoma of peritoneal dissemination

1)糖尿病组血管紧张素II诱导的去内皮大鼠离体主动脉收缩作用较非糖尿病组增强。七氟醚以浓度依赖性方式抑制肌张力，而异氟醚则无此作用。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来源于HSV-1，包含两种诱导细胞膜融合的机制。FusOn-H2衍生自HSV-2。Synco-2D和FusOn-H2在体外和体内均对多种肿瘤细胞有明显的杀伤作用。结果Synco-2D和FusOn-H2在体外均能杀伤人胃癌细胞，并能诱导细胞膜融合和凋亡。结论Synco-2D和FusOn-H2在体外和体内均能有效地杀伤人胃癌细胞，并能诱导胃癌细胞凋亡。 ...更多信息 比Baco-1容易得多。对于体内研究，将溶瘤病毒瘤内或静脉内给予荷有异种移植人胃癌的裸鼠，并在治疗后监测肿瘤生长速率和动物存活率。在大多数情况下，将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对异种移植的人胃癌产生了显著的效果，而Baco-1仅产生了中等的抗肿瘤活性。两次静脉注射。的Synco-2D也抑制了人胃癌异种移植物的生长，而Baco-1注射通过相同的途径缺乏任何可测量的抗肿瘤作用。在癌症患者中验证这些结果的临床试验似乎是必要的。少

1) The contraction of isolated rat aorta without endothelium induced by angiotensin II was enhanced in diabetic group compared with non-diabetic group. Sevoflurane inhibited the muscle tension in concentration-dependent manner, but isoflurane did not.Conditionally replicating (oncolytic) herpes simplex viruses (HSVs) have shown clear potential as effective agents for the treatment of solid tumors such as gastrointestinal cancer. 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.METHOD.We studied the in vitro and in vivo antitumor effects of both Synco-2D and FusOn-H2 against various type of cancer.RESULTS.Both Synco-2D and FusOn-H2 lysed human gastric cancer cells in v … More itro 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 gastric cancer, 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 nonfusogenic oncolytic HSV (Baco-1). A single intratumoral injection of either Synco-2D or FusOn-H2 produced a striking effect against xenografted human gastric cancer, in contrast to Baco-1, which produced only moderate antitumor activity. Two intravenous injections. of Synco-2D also inhibited the growth of human gastric cancer xenografts, while Baco-1 injections via the same route lacked any measurable antitumor effect.CONCLUSIONS.These data demonstrate that the newly constructed oncolytic HSVs have potent activity against established gastric cancer in animal models. Clinical trails to validate these results in cancer patients appear warranted. Less