建立癌症之選擇性化學療法-細菌標的腫瘤免疫特權區以進行即時 照影與治療

Bacteria enzyme pro-drug therapy

鮑韋伶(Wei-Ling Pao)

指導教授 ： 王照元

高雄醫學大學/醫學院/醫學研究所/碩士(2006年)

摘要

如何有效又具有選擇性的針對腫瘤部位進行治療，是目前癌症治療所要克服的難題。對於早期發現的腫瘤，治療方式多以外科手術佐以抗癌藥物，但是這樣的治療方法是有其限制的，譬如：腫瘤生長的區域必須是在可以開刀去除的部位，若腫瘤生長在太深部或腦部等較困難且危險的區域時，則不適用此方式治療；目前臨床所使用的抗癌藥物，除了能抑制腫瘤的生長外，抗癌藥物對於病患身體的副作用相當大，且對於較後期的癌症病患而言通常效果不佳。近幾年多篇論文陸續發表有關細菌可以在腫瘤所提供之免疫特權區生長，且厭氧菌對於腫瘤的惡質環境，例如缺乏養分、空氣等有良好適應能力，甚至是細菌的存在亦能引發腫瘤細胞生理病變誘發細胞凋亡。所以我們的治療策略希望能建立以細菌攜帶能夠催化葡萄糖酸甘前趨藥物(glucuronide prodrug)的β-葡萄糖醛酵素(Beta-glucuronidase βG)與冷光基因操縱子(LuxCDABE operon)的載體，利用細菌“tumor-finding”的特性，以非侵犯性照影系統追蹤細菌於個體免疫清除後局部放大座落於腫瘤處的時間點，於最適時間點施以前趨藥物療法，讓前趨藥物專一的只在腫瘤處被活化，達到非侵犯性即時追蹤細菌分佈與選擇性化學療法的目的。除此之外，我們以Lpp-OmpA細菌的外膜表現系統，表現可以專一結合於腫瘤細胞大量表現的腫瘤抗原蛋白的單鏈抗體 (single chain antibody, scFv)在細菌的外膜外部，如此細菌即可更專一的被侷限在腫瘤的免疫特權區部位，期望達到有效的治療效果並大大降低藥物活化後對非腫瘤處的傷害。

關鍵字

酵素前驅藥物療法 ； 醣醛酵素

並列摘要

In the cancer research area, people have long been seeking for a magic bullet that, in contrast to most current therapeutic methods, would selectively target and destroy malignant cells. Recently, many papers have shown that bacteria and viruses injected intravenously into live animals entered and replicated in solid tumor and metastases. Due to bacteria target tumor specifically, which has been used to transport and amplify genes encoding factors, such as pro-drug converting enzymes, toxins, angiogenesis inhibitors, and cytokines. We intend to establish the stable visualized bacteria by encoding luciferase-catalyzed luminescence (LuxCDABE) operon, which revealed the location of the tumors as visualized by real-time imaging, and encode the gene of β-glucuronidase (βG) that is a pro-drug converting enzyme to catalyze pro-drug into an active form and get rid of the tumors. Furthermore, we have used the microbial surface display system to present a single chain Fv (scFv) antibody fragment, consisting of the variable heavy and variable light domain from a monoclonal antibody (CC49 antibody), on the external surface of Escherichia coli by fusing it to an Lpp-OmpA hybrid previously shown to direct heterologous proteins to the cell surface. The CC49 antibody recognizes the tumor-associated glycoprotein TAG-72 of adenocarcinomas that can increase efficiency of bacterial tumor-binding and decrease administration of the bacterial dosage. We expect this strategy could work as well as decreasing the side effect of cancer therapy. This would be a novel platform for selective cancer therapy.

並列關鍵字

enzyme prodrug therapy ； betaG ； Lppompa

參考文獻

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