Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice

被引:261
作者
Zhao, Ming
Yang, Meng
Ma, Huaiyu
Li, Xiaoming
Tan, Xiuying
Li, Shukuan
Yang, Zhijian
Hoffman, Robert M.
机构
[1] AntiCancer Inc, San Diego, CA 92111 USA
[2] Univ Calif San Diego, Dept Surg, La Jolla, CA 92093 USA
关键词
D O I
10.1158/0008-5472.CAN-06-0716
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We report here a modified auxotrophic strain of Salmonella typhimurium that can target and cure breast tumors in orthotopic mouse models. We have previously reported development of a genetically modified strain of S. typhimurium, selected for prostate tumor targeting and therapy in vivo. The strain, termed S. typhimurium A1, selectively grew in prostate tumors in xenograft models causing tumor regression. In contrast, normal tissue was cleared of these bacteria even in immunodeficient athymic mice with no apparent side effects. A1 is auxotrophic (leucine-arginine dependent) but apparently receives sufficient nutritional support only from tumor tissue. The ability to grow in viable tumor tissue may account, in part, for the unique antitumor efficacy of the strain. In the present report, to increase tumor-targeting capability of A1, the strain was reisolated after infection of a human colon tumor growing in nude mice. The tumor-isolated strain, termed A1-R, had increased targeting for tumor cells in vivo as well as in vitro compared with A1. Treatment with A1-R resulted in highly effective tumor targeting, including viable tumor tissue and significant tumor shrinkage in mice with s.c. or orthotopic human breast cancer xerographs. Survival of the treated animals was significantly prolonged. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. These results suggest that amino acid auxotrophic virulent bacteria, which selectively infect and attack viable tumor tissue, are a promising approach to cancer therapy.
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收藏
页码:7647 / 7652
页数:6
相关论文
共 30 条
[1]   Bacteriolytic therapy can generate a potent immune response against experimental tumors [J].
Agrawal, N ;
Bettegowda, C ;
Cheong, I ;
Geschwind, JF ;
Drake, CG ;
Hipkiss, EL ;
Tatsumi, M ;
Dang, LH ;
Diaz, LA ;
Pomper, M ;
Abusedera, M ;
Wahl, RL ;
Kinzler, KW ;
Zhou, SB ;
Huso, DL ;
Vogelstein, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (42) :15172-15177
[2]   Relationship of sialyl-Lewisx/a underexpression and E-cadherin overexpression in the lymphovascular embolus of inflammatory breast carcinoma [J].
Alpaugh, ML ;
Tomlinson, JS ;
Ye, Y ;
Barsky, SH .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (02) :619-628
[3]   Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria [J].
Bettegowda, C ;
Dang, LH ;
Abrams, R ;
Huson, DL ;
Dillehay, L ;
Cheong, I ;
Agrawal, N ;
Borzillary, S ;
McCaffery, JM ;
Watson, EL ;
Lin, KS ;
Bunz, F ;
Baidoo, K ;
Pomper, MG ;
Kinzler, KW ;
Vogelstein, B ;
Zhou, SB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (25) :15083-15088
[4]  
Brown JM, 1998, CANCER RES, V58, P1408
[5]   Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium [J].
Clairmont, C ;
Lee, KC ;
Pike, J ;
Ittensohn, M ;
Low, KB ;
Pawelek, J ;
Bermudes, D ;
Brecher, SM ;
Margitich, D ;
Turnier, J ;
Li, Z ;
Luo, X ;
King, I ;
Zheng, LM .
JOURNAL OF INFECTIOUS DISEASES, 2000, 181 (06) :1996-2002
[6]  
Coley WB, 1906, AM J MED SCI, V131, P375
[7]   Combination bacteriolytic therapy for the treatment of experimental tumors [J].
Dang, LH ;
Bettegowda, C ;
Huso, DL ;
Kinzler, KW ;
Vogelstein, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :15155-15160
[8]   Pharmacologic and toxicologic evaluation of C-novyi-NT spores [J].
Diaz, LA ;
Cheong, I ;
Foss, CA ;
Zhang, XS ;
Peters, BA ;
Agrawal, N ;
Bettegowda, C ;
Karim, B ;
Liu, GS ;
Khan, K ;
Huang, X ;
Kohli, M ;
Dang, LH ;
Hwang, P ;
Vogelstein, A ;
Garrett-Mayer, E ;
Kobrin, B ;
Pomper, M ;
Zhou, SB ;
Kinzler, KW ;
Vogelstein, B ;
Huso, DL .
TOXICOLOGICAL SCIENCES, 2005, 88 (02) :562-575
[9]  
Forbes NS, 2003, CANCER RES, V63, P5188
[10]  
Fox ME, 1996, GENE THER, V3, P173