Bolyard Chelsea, Yoo Ji Young, Wang Pin-Yi, Saini Uksha, Rath Kellie S, Cripe Timothy P, Zhang Jianying, Selvendiran Karuppaiyah, Kaur Balveen
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University, Columbus, Ohio.
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
Clin Cancer Res. 2014 Dec 15;20(24):6479-94. doi: 10.1158/1078-0432.CCR-14-0463. Epub 2014 Oct 7.
Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell-specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer.
Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites-derived tumor cells, and primary patient ascites-derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou-Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer.
Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites-derived and patient ascites-derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors.
This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer.
需要新的治疗方案来改善晚期卵巢癌的不良预后。溶瘤病毒目前正在卵巢癌患者中进行测试。在此，我们测试了将阿霉素与34.5ENVE联合使用的治疗效果，34.5ENVE是一种由修饰的干细胞特异性巢蛋白启动子转录驱动的溶瘤单纯疱疹病毒，编码抗血管生成的血管抑素-120（VStat120），用于治疗进展期卵巢癌。
通过标准MTT法评估34.5ENVE在卵巢癌细胞系、小鼠腹水来源的肿瘤细胞和原发性患者腹水来源的肿瘤细胞中的抗肿瘤效果。通过Transwell小室分析法测量34.5ENVE感染的卵巢癌细胞条件培养基抑制内皮细胞迁移的能力。使用Chou-Talalay协同分析评估34.5ENVE与阿霉素之间细胞毒性相互作用的范围。评估病毒复制、单纯疱疹病毒受体表达和细胞凋亡情况。在人卵巢癌的小鼠异种移植模型中体内评估溶瘤病毒疗法与阿霉素联合使用的疗效。
用34.5ENVE处理可降低卵巢癌细胞系、小鼠腹水来源和患者腹水来源的卵巢肿瘤细胞的活力。34.5ENVE感染的肿瘤细胞条件培养基可减少内皮细胞迁移。当与阿霉素联合使用时，34.5ENVE具有协同杀伤作用，半胱天冬酶-3/7激活显著增加，细胞亚G1期群体增加。阿霉素与34.5ENVE联合使用可显著延长携带腹膜内卵巢癌肿瘤的裸鼠的生存期。
本研究表明34.5ENVE单独使用以及与阿霉素联合使用对播散性腹膜卵巢癌具有显著的抗肿瘤效果。
