Nakamori Mikihito, Fu Xinping, Meng Feng, Jin Aiwu, Tao Lihua, Bast Robert C, Zhang Xiaoliu
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Clin Cancer Res. 2003 Jul;9(7):2727-33.
Replication-competent herpes simplex virus [HSV (oncolytic HSV)] holds considerable promise for treating malignant solid tumors, although the potency of the virus needs improvement if its full clinical potential is to be realized. Incorporation of membrane fusion capability into an oncolytic HSV, either by screening for a syncytial HSV mutant after random mutagenesis or by inserting a hyperfusogenic glycoprotein from gibbon ape leukemia virus into the viral genome, can significantly enhance the antitumor effects of the virus (X. Fu and X. Zhang, Cancer Res., 62: 2306-2312, 2002; X. Fu et al., Mol. Ther., in press, 2003). We reasoned that both fusogenic strategies, incorporated into a single oncolytic HSV, might significantly improve virotherapy for ovarian cancer.
In vitro characterization of a doubly fusogenic oncolytic HSV (Synco-2D) showed that this virus produces a distinctive syncytial phenotype, leading to a significantly increased tumor cell killing ability, compared with that of a nonfusogenic virus. When injected directly into the abdominal cavity of mice bearing human ovarian cancer xenografts, Synco-2D eradicated all tumor masses in 75% of the animals, whereas no animals in the conventional oncolytic HSV-treated group were tumor free.
This newly generated fusogenic oncolytic HSV is a promising candidate for clinical testing against advanced ovarian cancer.
具有复制能力的单纯疱疹病毒[HSV（溶瘤性HSV）]在治疗恶性实体瘤方面具有巨大潜力，不过要充分发挥其临床潜力，该病毒的效力仍有待提高。通过在随机诱变后筛选形成多核细胞的HSV突变体，或将长臂猿白血病病毒的高融合性糖蛋白插入病毒基因组，从而将膜融合能力整合到溶瘤性HSV中，可显著增强该病毒的抗肿瘤效果（傅X和张X，《癌症研究》，62：2306 - 2312，2002；傅X等人，《分子治疗》，即将发表，2003）。我们推断，将这两种融合策略整合到单一的溶瘤性HSV中，可能会显著改善卵巢癌的病毒疗法。
对双重融合性溶瘤性HSV（Synco - 2D）进行的体外特性分析表明，与非融合性病毒相比，该病毒产生独特的多核细胞表型，导致肿瘤细胞杀伤能力显著增强。当直接注射到携带人卵巢癌异种移植瘤的小鼠腹腔中时，Synco - 2D使75%的动物体内所有肿瘤块消失，而在传统溶瘤性HSV治疗组中，没有动物无瘤。
这种新产生的融合性溶瘤性HSV是针对晚期卵巢癌进行临床试验的有前景的候选药物。
