The development of a novel genetherapy for pelitoneal dissemination of ovarian cancer using HSV-1 and its amplicon system.

使用 HSV-1 及其扩增子系统开发一种针对卵巢癌腹腔播散的新型基因疗法。

• 批准号: 15591791
• 负责人: NAWA Akihiro
• 金额: $ 2.24万
• 依托单位: Nagoya University (2005)Aichi Cancer Center Research Institute (2003-2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591791/
• 关键词: HSV amplicon; rabbit-carboxyl esterase; taxol prodrug; MDR expressing cells; clear cell carcinoma cells of the ovary; rabbit-carboxlesterase; HSV; タキソール ブロドラック; アンプリコン; Rabbit carboxylesterase; MDR; タキソール プロドラッグ; Rabbit Carboxylesterase

We demonstrated that oncolytic HSV 1 mutants very effectively treated peritoneally disseminated ovarian cancer in a mouse model.To aid in the development of paclitaxel (TAX) prodrugs for gene-directed enzyme prodrug therapy (GDEPT), we examined the cytotoxicity of TAX-2'-Et in a human clear cell carcinoma of the ovary cell line (KOC-7c), which had been transfected with a rabbit carboxylesterase (Ra-CES) cDNA. Transfection of Ra-CES into MDR(P-gp)-expressing KOC-7c cells conferred a high level of TAX-2'-Et cytotoxicity via prodrug activation. The intracellular levels of TAX for a specific exposure time were significantly increased in cells treated with TAX-2'-Et in Ra-CES-positive KOC-7c cells over the levels seen in TAX-treated cells. In conclusion, TAX-2'-Et can circumvent P-gp-associated cellular efflux of TAX. TAX-2'-Et is converted into TAX by the Ra-CES, supporting its potential use as a theoretical GDEPT strategy for TAX therapy. The TAX-2'-Et prodrug efficiently increased the amount of intracellular TAX, which mediates tumor cell death. Moreover, we have developed a virus cocktail containing HSV1 HF-10 and HSV1 amplicon expressing Ra-CES in the ratio of 1:5. We are examining an efficacy of the combination of the cocktail and TAX-2'-Et to the KOC-7c cells, which reveal TAX-resistance markedly.

我们证明溶瘤 HSV 1 突变体非常有效地治疗小鼠模型中的腹膜播散性卵巢癌。 为了帮助开发用于基因定向酶前药疗法 (GDEPT) 的紫杉醇 (TAX) 前药，我们检查了 TAX-2'-Et 在人类卵巢细胞系透明细胞癌 (KOC-7c) 中的细胞毒性，该细胞已被 用兔羧酸酯酶 (Ra-CES) cDNA 转染。将 Ra-CES 转染至表达 MDR(P-gp) 的 KOC-7c 细胞中，通过前药激活赋予高水平的 TAX-2'-Et 细胞毒性。在 Ra-CES 阳性 KOC-7c 细胞中，用 TAX-2'-Et 处理的细胞中，特定暴露时间的 TAX 细胞内水平显着高于 TAX 处理细胞中的水平。总之，TAX-2'-Et 可以规避 P-gp 相关的 TAX 细胞外流。 TAX-2'-Et 由 Ra-CES 转化为 TAX，支持其作为 TAX 治疗的理论 GDEPT 策略的潜在用途。 TAX-2'-Et 前药有效增加细胞内 TAX 的量，从而介导肿瘤细胞死亡。此外，我们还开发了一种以1:5的比例含有HSV1 HF-10和表达Ra-CES的HSV1扩增子的病毒混合物。我们正在研究混合物和 TAX-2'-Et 组合对 KOC-7c 细胞的功效，这显着揭示了 TAX 抗性。

项目成果

Association of XRCC1 Arg399Gln and OGG1 Ser326Cys polymorphisms with the risk of cervical cancer in Japanese subjects

• DOI: 10.1016/j.ygyno.2005.05.018
• 发表时间: 2005-10-01
• 期刊: GYNECOLOGIC ONCOLOGY
• 影响因子: 4.7
• 作者: Niwa, Y;Matsuo, K;Hamajima, N
• 通讯作者: Hamajima, N

Association of p73 G4C14-TO-A4T14 polymorphism at exon 2 and p53 Arg72Pro polymorphism with the risk of endometrial cancer in Japanese subject.

p73 G4C14-TO-A4T14 外显子 2 多态性和 p53 Arg72Pro 多态性与日本受试者子宫内膜癌风险的关联。

• 发表时间: 2005
• 期刊: Cancer Lett 219
• 作者: Hozumi Y;Ito T;Nakano T;Nakagawa T;Aoyagi M;Kondo H;Goto K.;Kazuhiko Ino;Chihiro Kondo;Yoshimitsu Niwa;Yoshimitsu Niwa
• 通讯作者: Yoshimitsu Niwa

Takakuwa H.et al.: "Oncolytic viral therapy using a spontaneously generated herpes simplex virus type1 variant for disseminated peritoneal tumor in immunocompetent mice"Archives of Virology. 148. 813-825 (2003)

Takakuwa H.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治疗，用于免疫活性小鼠的播散性腹膜肿瘤”病毒学档案。

Retroviral vector backbone immunogenicity: identification of cytotoxic T-cell epitopes in retroviral vector-packaging sequences

• DOI: 10.1038/sj.gt.3302406
• 发表时间: 2005-02-01
• 期刊: GENE THERAPY
• 影响因子: 5.1
• 作者: Kondo, E;Akatsuka, Y;Takahashi, T
• 通讯作者: Takahashi, T

Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumor angiogenesis and patient survival.

卵巢癌中血管紧张素 II 1 型受体的表达及其与肿瘤血管生成和患者生存的相关性。

• 发表时间: 2006
• 期刊: Br J Cancer 94
• 作者: Kondo C et al.;Ino K et al.
• 通讯作者: Ino K et al.