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

点击翻译按钮获取中文摘要

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.