Hoffman Robert M
AntiCancer Inc., San Diego, CA 92111, USA.
Amino Acids. 2009 Sep;37(3):509-21. doi: 10.1007/s00726-009-0261-8. Epub 2009 Mar 17.
We have developed an effective bacterial cancer therapy strategy by targeting viable tumor tissue using Salmonella typhimurium auxotrophs that we have generated which grow in viable as well as necrotic areas of tumors. However, the auxotrophy severely restricts growth of these bacteria in normal tissue. The S. typhimurium A1-R mutant, which is auxotrophic for leu-arg and has high anti-tumor virulence, was developed in our laboratory. In vitro, A1-R infects tumor cells and causes nuclear destruction. A1-R was initially used to treat metastatic human prostate and breast tumors that had been orthotopically implanted in nude mice. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. A1-R administered i.v. to nude mice with primary osteosarcoma and lung metastasis was highly effective, especially against metastasis. A1-R was also targeted to both axillary lymph and popliteal lymph node metastasis of human pancreatic cancer and fibrosarcoma, respectively, as well as lung metastasis of the fibrosarcoma in nude mice. The bacteria were delivered via a lymphatic channel to target the lymph node metastases and systemically via the tail vein to target the lung metastasis. The metastases were cured without the need of chemotherapy or any other treatment. A1-R was administered intratumorally to nude mice with an orthotopically transplanted human pancreatic tumor. The primary pancreatic cancer regressed without additional chemotherapy or any other treatment. A1-R was also effective against pancreatic cancer liver metastasis when administered intrasplenically to nude mice. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. Three promoter clones engineered in S. enterica typhimurium were identified to have enhanced expression in bacteria growing in tumors relative to those growing in the spleen. The expression of therapeutics in Salmonella under the regulation of one or more promoters that are activated preferentially in tumors has the potential to improve the efficacy of Salmonella tumor therapy. Exploitation of the tumor-killing capability of Salmonella has great promise for a new paradigm of cancer therapy.
我们通过使用鼠伤寒沙门氏菌营养缺陷型菌株靶向活肿瘤组织，开发出了一种有效的细菌癌症治疗策略。我们所构建的这些营养缺陷型菌株能在肿瘤的活组织区域以及坏死区域生长。然而，营养缺陷严重限制了这些细菌在正常组织中的生长。鼠伤寒沙门氏菌A1-R突变体是我们实验室构建的，它对亮氨酸-精氨酸营养缺陷，且具有高抗肿瘤毒力。在体外，A1-R能感染肿瘤细胞并导致细胞核破坏。A1-R最初用于治疗原位植入裸鼠体内的转移性人前列腺癌和乳腺癌。40%接受治疗的小鼠被完全治愈，并且存活时间与未患肿瘤的小鼠一样长。将A1-R静脉注射给患有原发性骨肉瘤和肺转移的裸鼠，效果非常显著，尤其是对转移灶。A1-R还分别靶向人胰腺癌和纤维肉瘤的腋窝淋巴结转移以及腘窝淋巴结转移，以及裸鼠体内纤维肉瘤的肺转移。细菌通过淋巴管输送以靶向淋巴结转移灶，并通过尾静脉全身输送以靶向肺转移灶。这些转移灶无需化疗或任何其他治疗即可治愈。将A1-R瘤内注射给原位移植人胰腺肿瘤的裸鼠。原发性胰腺癌在无需额外化疗或任何其他治疗的情况下消退。当将A1-R脾内注射给裸鼠时，它对胰腺癌肝转移也有效。这里所描述的方法，即细菌单一疗法能有效治疗原发性和转移性肿瘤，相较于以往需要与毒性化疗联合使用的细菌肿瘤治疗策略有显著改进。在鼠伤寒沙门氏菌中构建的三个启动子克隆被鉴定出相对于在脾脏中生长的细菌，在肿瘤中生长的细菌中具有增强的表达。在一个或多个优先在肿瘤中被激活的启动子调控下，沙门氏菌中治疗性物质的表达有可能提高沙门氏菌肿瘤治疗的疗效。利用沙门氏菌的肿瘤杀伤能力对癌症治疗的新范式具有巨大潜力。
