於自然界中，某些兼性厭氧或絕對厭氧的細菌在臨床及動物實驗中發現，可以專一地標定到腫瘤並且在腫瘤中複製繁殖。似乎利用細菌來治療腫瘤是一種新的治療策略。在此研究中，我們證實減毒豬霍亂沙門氏桿菌可作為抑制血管新生基因治療載體甚至發現其本身就具有抵抗腫瘤生長的能力。首先利用減毒豬霍亂沙門氏桿菌攜帶報告基因，全身性給予帶有腫瘤的小鼠中，發現攜帶基因的減毒豬霍亂沙門氏桿菌大量聚集於腫瘤中，並且可以將基因大量傳達至腫瘤。這樣一個現象可維持至少十天以上，且其報告基因於腫瘤中表達的強度遠高於其他正常器官的1800倍以上。於是當利用減毒豬霍亂沙門氏桿菌攜帶抗血管新生基因來對抗腫瘤時，發現不僅僅可以明顯的抑制小鼠腫瘤的生長並且延長其存活率。在腫瘤組織切片中也發現這樣的一個策略，減少了腫瘤中血管的密度、降低血管內皮細胞生長因子的表現量且有更多的免疫細胞浸潤於腫瘤中。再者我們也利用減毒豬霍亂沙門氏桿菌合併低計量的化療藥劑，於小鼠模式評估其對好發於國人的肝癌及肺癌之治療效果。將減毒豬霍亂沙門氏桿菌利用腹腔注射入帶有腫瘤的小鼠，也同樣發現減毒豬霍亂沙門氏桿菌不僅可以抑制皮下腫瘤的生長並且對於轉移的腫瘤一樣具有療效。當減毒豬霍亂沙門氏桿菌合併低計量的cisplatin時發現有增加減毒豬霍亂沙門氏桿菌抑制腫瘤生長的能力並更加延長小鼠存活率。在此一方式治療下，發現更多嗜中性球及CD8+ T細胞浸潤於腫瘤中且增加更多死亡的腫瘤細胞。由實驗結果發現減毒豬霍亂沙門氏桿菌不僅可作為基因治療的載體，且本身具有的腫瘤裂解及吸引免疫細胞浸潤腫瘤的能力，再合併其他傳統的治療方法下更加提升其療效，對於原位甚至是轉移的腫瘤都可以提供另一種選擇及思考方向。

　Some anaerobic and facultatively anaerobic bacteria have been used experimentally as anticancer agents because of their selective growth in tumors. In this study, we exploited attenuated Salmonella choleraesuis as a vector to deliver antiangiogenic genes for tumor-targeted gene therapy and a tumoricidal agent. Attenuated S. choleraesuis carrying reporter genes was used to evaluate its abilities of preferential accumulation and gene delivery in tumor sites. Transgene expression via S. choleraesuis-mediated gene transfer also persisted for at least 10 days in tumor sites. The level of transgene expression via S. choleraesuis-mediated gene transfer in tumors could reach more than 1800-fold higher than in livers and spleens. When administered into mice bearing subcutaneous or pulmonary metastatic tumors, S. choleraesuis carrying antiangiogenic genes significantly inhibited tumor growth and enhanced survival of the mice. Furthermore, immunohistochemical studies in the tumors revealed decreased intratumoral microvessel density, reduced expression of vascular endothelial growth factor (VEGF), and increased infiltration of CD8+ T cells. We also demonstrated S. choleraesuis as a single-agent therapy and as part of a combination therapy with low-dose cisplatin for syngeneic murine lung tumor and hepatoma. S. choleraesuis was also capable of delaying tumor growth and enhancing survival in both subcutaneous tumor and experimental metastasis models. More strikingly, the combination of S. choleraesuis plus cisplatin acted additively to retard tumor growth and extensively prolong the survival time of the mice bearing hepatomas or lung tumors. Such combination treatment also increased infiltrating neutrophils and CD8+ T cells, as well as apoptotic cells in the tumors. These findings suggest that S. choleraesuis, which exerts oncolytic effects and enhances antitumor immune responses, represents a promising strategy for the treatment of primary and metastatic tumors.

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