Oncolytic viral therapy for disseminated peritoneal ovarian cancer using a novel replication-competent herpes simplex virus type 1 mutant in mice.

使用新型具有复制能力的 1 型单纯疱疹病毒突变体对小鼠进行溶瘤病毒治疗，用于治疗播散性腹膜卵巢癌。

• 批准号: 13671760
• 负责人: NAWA Akihiro
• 金额: $ 2.37万
• 依托单位: Aichi Cancer Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671760/
• 关键词: replication-competent; herpes simplexvirus type1 mutant; ovarian cancer; peritoneally disseminated neoplasm; mouse model; syncytial formation; apoptosis; immuno-competent mouse; 増殖型HSVI変異株

We prepared two attenuated mutant HSV-1 strains. One is an HSV-1 mutant, hrR3, and another is a new replication competent HSV-1 mutant, HR522 ; this virus, expressing the lacZ reporter gene, induces syncytium formation in infected cells. We compared the efficacy of HR522 with Taxol and hrR3 in the treatment of nude mice harboring human ovarian cancer cells. We also examined the effect of the prodrug ganciclovir (GCV) on the treatment mediated by these HSVs. The survival of mice treated with a high titer hrR3 (5x10^7 plaque-forming units ; PFU) was significantly prolonged as compared to the group given Taxol (p<0.0001 ; Log-Rank test). Although the survival of mice treated with high titer HR522 (5x10^7 PFU) was not significantly prolonged compared with Taxol-treated group (p=0.212 ; Log-Rank test), GCV markedly enhanced the efficacy of HR522 administration (p<0.005 ; vs Taxol ; Log-Rank test). The lacZ gene product, visualized using 5-brorno-4-chrolo-3-indoryl-β-D- galactopyranoside (X-gal) histochemistry, was detected in HR522-treated tumors in areas also exhibiting apoptotic changes. Another study demonstrated that a clonal derivative of HSV-1 strain HF done 10 very effectively treated peritoneally disseminated neoplasm in an immunocompetent animal model and that all of survived mice acquired resistance to rechallenge of tumor cells. HF clone 10 induces syncytia formation in vitro. A sequential administration ofHF clone 10 attained a long-term survival over 90 days after tumor injection in 8 of the 9 treated mice without any signs of diseases. The results suggested that treatment of peritoneally disseminated tumor with HF clone 10 induced a specific anti-tumor immune response. We found that clone 10 has a deletion of 39kbp in the right end of UL and UL/IRL junction, resulting in the loss of UL 56 expression. Moreover, a 23kbp deletion and extensive rearrangement were observed in the left end of the genome.

我们准备了两个减弱的突变HSV-1菌株。一个是HSV-1突变体HRR3，另一个是一种新的复制型HSV-1突变体HR522；该病毒表达了LACZ报告基因，可在被感染的细胞中诱导合胞体形成。我们将HR522与紫杉醇和HRR3的有效性进行了比较，在治疗具有人类卵巢癌细胞的裸小鼠方面。我们还研究了前药Ganciclovir（GCV）对这些HSV介导的处理的影响。与给定的紫杉醇组相比，用高滴度HRR3（5x10^7斑块形成单位； PFU）处理的小鼠的存活显着延长（p <0.0001；对数秩检验）。尽管与紫杉醇治疗组相比，用高滴度HR522（5x10^7 PFU）治疗的小鼠的存活量没有显着延长（P = 0.212；对数秩检验），但GCV显着提高了HR522给药的效率（p <0.005; vs taxol-log-and-lank-and-lank-and-and-lank test; LACZ基因产物使用5-BRORNO-4-CHROLO-3-INDORYL-β-D-半乳糖苷（X-GAL）组织化学观察到，在HR522处理的肿瘤中也检测到凋亡变化的区域。另一项研究表明，HSV-1菌株HF的克隆衍生物进行了10次在免疫能力动物模型中非常有效治疗的腹膜散布肿瘤，并且所有幸存的小鼠都获得了对肿瘤细胞的抗性性的耐药性。 HF克隆10在体外诱导合胞体形成。 HF克隆10的顺序给药在肿瘤注射后90天内的长期生存附着在90天中的8例治疗小鼠中，没有任何疾病迹象。结果表明，用HF克隆10治疗腹膜传播肿瘤会诱导特定的抗肿瘤免疫响应。我们发现，克隆10在UL和UL/IRL连接的右端缺失了39kbp，导致UL 56表达的丧失。此外，在基因组的左端观察到了23kbp缺失和广泛的重排。

项目成果

Nicolson GL, Nawa A, et al.: "Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation"Clinical experimental metastasis. (in press).

Nicolson GL、Nawa A等人：“肿瘤转移相关的人MTA1基因及其MTA1蛋白产物：在上皮癌细胞侵袭、增殖和核调节中的作用”临床实验转移。

Takakuwa H, Nawa A, Nishiyama Y, et al.: "Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for peritoneally disseminated tumor in immunocompetent mice"Archives of Virology. (in press).

Takakuwa H、Nawa A、Nishiyama Y 等人：“使用自发产生的单纯疱疹病毒 1 型变体进行溶瘤病毒疗法，用于免疫活性小鼠的腹膜播散性肿瘤”病毒学档案。