Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
Cancer Gene Ther. 2010 Jan;17(1):11-9. doi: 10.1038/cgt.2009.44.
Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1-10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 microM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1-10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg(-1)) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.
尽管过去几十年在卵巢癌的化疗方面取得了巨大进展，但对于有大量腹膜播散的晚期病例，其预后仍不理想，因此迫切需要结合化疗的新型治疗方法。我们最近使用端粒酶特异性复制选择性腺病毒（Telomelysin：OBP-301）开发了实体瘤的病毒疗法，其中已插入人端粒酶逆转录酶（hTERT）基因启动子以指导肿瘤特异性 E1 基因表达。在这项研究中，我们研究了 OBP-301 与顺铂（CDDP）联合治疗卵巢癌细胞的抗肿瘤作用。在感染复数（MOI）为 0.01-100 时，SKOV3 细胞的体外 OBP-301 处理以剂量依赖性方式诱导显著的细胞死亡，MOI 为 1-10 时具有中等细胞毒性，MOI 为 100 时具有最大细胞毒性。相比之下，MOI 为 1-10 时，OBP-301 处理正常人细胞不会引起明显的细胞死亡，而 MOI 为 100 时会引起适度的细胞毒性。低剂量 CDDP（0.5-1 microM）诱导仅 20%的细胞死亡，与 MOI 为 1-10 的 OBP-301 联合使用可显著增强其效果，最终达到 40%的细胞死亡。在 CDDP 耐药卵巢癌细胞中也观察到 CDDP 敏感性的这种增强。在具有腹膜播散的 SKOV3 的异种移植小鼠模型中进一步测试了联合作用。腹腔内给予 OBP-301 后，我们通过荧光成像证实，注射的与绿色荧光蛋白（GFP）基因融合的 OBP-301（OBP-401）优先定位于腹膜播散部位。用低剂量（0.5mgkg(-1)）CDDP 治疗小鼠效果适度，播散减少 10%，而与 MOI 为 10 的腹腔内给予 OBP-301 联合使用可增强效果，播散减少约 80%。Kaplan-Meier 分析表明，与单独使用 CDDP 相比，用 CDDP 加 OBP-301 治疗的小鼠总生存期得到改善。这些发现支持腹腔内给予 OBP-301 以增加卵巢癌细胞对 CDDP 的敏感性的治疗潜力。
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