期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 24, 页码 10170-10174出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0703867104
关键词
amino acid auxotrophy; bacterial therapy; antitumor efficacy; imaging
资金
- NCI NIH HHS [R43 CA119841, CA 103563, R44 CA103563, CA 119841, R43 CA103563] Funding Source: Medline
Bacterial infection occasionally has a marked therapeutic effect on malignancies, as noted as early as the 19th century. Recently, there have been attempts to develop cancer treatment by using tumor-targeting bacteria. These treatments were developed to deliver therapeutic molecules specifically to tumors. Researchers used anaerobic microorganisms that preferentially grew in necrotic tumor areas. However, the resulting tumor killing was, at best, limited. We have developed a far more effective bacterial cancer therapy by targeting viable tumor tissue by using Salmonella typhimurium leu-arg auxotrophs. Although these bacteria grow in viable as well as necrotic areas of tumors, the nutritional auxotrophy severely restricts growth in normal tissue. In the current study, we measured the antitumor efficacy of the S. typhimurium A1-R mutant, which is auxotrophic for leu-arg and has increased antitumor virulence selected by tumor passage. A1-R was used to treat metastatic PC-3 human prostate tumors that had been orthotopically implanted in nude mice. GFP was used to image tumor and metastatic growth. Of the 10 mice with the PC-3 tumors that were injected weekly with S. typhimurium A1-R, 7 were alive and well at the time the last untreated mouse died. Four Al-R-treated mice remain alive and well 6 months after implantation. Ten additional nontumor-bearing mice were injected weekly to determine the toxicity of S. typhimurium A1-R. No toxic effects were observed. The approach described here, where bacterial monotherapy effectively treats metastatic prostate tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy.
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