Lee Che-Hsin, Wu Chao-Liang, Shiau Ai-Li
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
J Gene Med. 2004 Dec;6(12):1382-93. doi: 10.1002/jgm.626.
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 tumoricidal agent and a vector to deliver the endostatin gene for tumor-targeted gene therapy.
Attenuated S. choleraesuis carrying a eukaryotic expression plasmid encoding reporter gene was used to evaluate its abilities of tumor targeting and gene delivery in three syngeneic murine tumor models. Furthermore, S. choleraesuis carrying the endostatin expression vector was administered intraperitoneally into tumor-bearing mice, and its antitumor effect was evaluated.
Systemically administered S. choleraesuis preferentially accumulated within tumors for at least 10 days, forming tumor-to-normal tissue ratios exceeding 1000-10,000 : 1. Transgene expression via S. choleraesuis-mediated gene transfer also persisted for at least 10 days. Host immune responses and tumor hypoxia may influence tumor-targeting potential of S. choleraesuis. When systemically administered into mice bearing melanomas or bladder tumors, S. choleraesuis carrying the endostatin expression vector significantly inhibited tumor growth by 40-70% and prolonged 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.
These results suggest that tumor-targeted gene therapy using S. choleraesuis carrying the endostatin expression vector, which exerts tumoricidal and antiangiogenic activities, represents a promising strategy for the treatment of solid tumors.
一些厌氧和兼性厌氧细菌因其在肿瘤中的选择性生长而被用于实验性抗癌治疗。在本研究中，我们利用减毒猪霍乱沙门氏菌作为肿瘤杀伤剂和载体，用于递送内皮抑素基因进行肿瘤靶向基因治疗。
携带编码报告基因的真核表达质粒的减毒猪霍乱沙门氏菌，用于评估其在三种同基因小鼠肿瘤模型中的肿瘤靶向和基因递送能力。此外，将携带内皮抑素表达载体的猪霍乱沙门氏菌腹腔注射到荷瘤小鼠体内，并评估其抗肿瘤效果。
全身给药的猪霍乱沙门氏菌在肿瘤内优先聚集至少10天，肿瘤与正常组织的比例超过1000 - 10000:1。通过猪霍乱沙门氏菌介导的基因转移的转基因表达也持续至少10天。宿主免疫反应和肿瘤缺氧可能影响猪霍乱沙门氏菌的肿瘤靶向潜力。当全身给药于携带黑色素瘤或膀胱肿瘤的小鼠时，携带内皮抑素表达载体的猪霍乱沙门氏菌显著抑制肿瘤生长40% - 70%，并延长小鼠存活时间。此外，肿瘤的免疫组化研究显示肿瘤内微血管密度降低、血管内皮生长因子（VEGF）表达减少以及CD8(+) T细胞浸润增加。
这些结果表明，使用携带内皮抑素表达载体的猪霍乱沙门氏菌进行肿瘤靶向基因治疗，具有肿瘤杀伤和抗血管生成活性，是一种有前景的实体瘤治疗策略。
