A genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer.
A genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer.
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一种用于胰腺癌肿瘤治疗的基因增强厌氧细菌。
DOI：
10.1093/jnci/djn308
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Woo,SavioLC
中科院分区：
文献类型：
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作者：
Li,Zhiyu;Fallon,John;Mandeli,John;Wetmur,James;Woo,SavioLC
背景治疗实体瘤的一个主要障碍是治疗药物不能有效地输送到低氧核心。缺氧为厌氧菌定植和细菌破坏肿瘤提供了可能，野生型产气荚膜梭菌（Cp）的休眠孢子在小鼠胰腺肿瘤的缺氧核心内萌发和增殖。然而，Cp的肿瘤作用受到宿主炎症反应和Cp对氧的残余耐受性的限制，从而在动物中引起毒性作用。方法构建缺失主要耐氧基因超氧化物歧化酶（Cp/sod -）的重组Cp菌株，增强其在肿瘤中的选择性生长。此外，将一种来自金黄色葡萄球菌的炎症抑制基因pton - valentine Leukocidin （PVL）插入到Cp/sod -基因组中，以增强其致癌作用。在携带小鼠PANC02肿瘤的C57/BL6小鼠中研究了重组Cp菌株对肿瘤的杀伤能力。通过监测血清化学和组织病理学检查评估全身和器官毒性作用。统计检验是双侧的。结果将Cp/sod -孢子静脉注射到荷瘤小鼠中，与野生型Cp相比，Cp/sod -的毒性作用降低。与野生型Cp和Cp/sod -孢子处理的小鼠相比，用Cp/sod - /PVL孢子处理的小鼠肿瘤中中性粒细胞和巨噬细胞减少，瘤内细菌的生长呈对数增长，肿瘤坏死增强，存活时间大大延长，没有明显的全身和器官毒性作用。因此，47%的Cp/sod - / pvl处理的小鼠（n = 15）达到了120天以上的无瘤生存，而所有用Cp/sod -或磷酸盐缓冲盐水处理的小鼠（每组n = 10）在50天内死亡。Cp/sod - / pvl处理小鼠的中位生存期为77天（95%可信区间[CI] = 45 ~ 120天），Cp/sod -处理小鼠的中位生存期为30天（95% CI = 23 ~ 36天；P < .001）。结论Cp/sod - /PVL为一类新型的肿瘤病原微生物提供了一个原型，这些微生物可能具有安全有效治疗胰腺癌和其他血管化不良肿瘤的潜力。
Background A major obstacle in treatment of solid tumors is the inefficient delivery of therapeutic agents to the hypoxic cores. Hypoxia offers the potential for anaerobic bacteria colonization and tumor destruction by the bacteria, and dormant spores of wild-type Clostridium perfringens (Cp) germinate and proliferate within the hypoxic cores of pancreatic tumors in mice. However, the oncopathic effects of Cp were limited by host inflammatory responses and by Cp ’ s residual tolerance to oxygen, which caused toxic effects in animals. Methods Recombinant Cp strains in which superoxide dismutase, a major oxygen tolerance gene, was deleted (Cp/sod−) were constructed to enhance its selective growth in tumors. In addition, Panton-Valentine Leukocidin (PVL), an inflammation-suppressing gene from Staphylococcus aureus, was inserted into the Cp/sod− genome to enhance its oncopathic potency. The ability of the recombinant Cp strains to kill tumors was investigated in C57/BL6 mice bearing murine PANC02 tumors. Systemic and organ toxic effects were assessed by monitoring serum chemistries and histopathological examination. Statistical tests were two-sided. Results Cp/sod− showed reduced toxic effects compared with wild-type Cp when spores were administered intravenously into PANC02 tumor–bearing mice. Mice treated with Cp/sod−/PVL spores demonstrated a reduction in neutrophils and macrophages in tumors, logarithmically elevated growth of intratumoral bacteria, enhanced tumor necrosis, and substantially prolonged survival without apparent systemic and organ toxic effects, compared with mice treated with both wild-type Cp and Cp/sod− spores. Accordingly, 47% of Cp/sod−/PVL–treated mice (n = 15) achieved tumor-free survival for over 120 days, whereas all mice treated with Cp/sod− or phosphate-buffered saline (n = 10 per group) died within 50 days. The median survival for Cp/sod−/PVL–treated mice was 77 days (95% confidence interval [CI] = 45 to 120 days) and for Cp/sod−–treated mice was 30 days (95% CI = 23 to 36 days; P < .001). Conclusions Cp/sod−/PVL provides a prototype for a novel class of oncopathic microbes that may have potential for the safe and effective treatment of pancreatic cancer and other poorly vascularized tumors.