Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models

We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmo...

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Bibliographic Details
Published in:PloS one 2015-06, Vol.10 (6), p.e0120358-e0120358
Main Authors: Hiroshima, Yukihiko, Zhang, Yong, Zhao, Ming, Zhang, Nan, Murakami, Takashi, Maawy, Ali, Mii, Sumiyuki, Uehara, Fuminari, Yamamoto, Mako, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, Hoffman, Robert M
Format: Article
Language:English
Subjects:
Animal models
Animals
Body weight
Body weight loss
Bone cancer
Breast cancer
Cancer
Cancer therapies
Cell cycle
Cervical cancer
Cervix
Chemotherapy
Disease Models, Animal
Effectiveness
ErbB-2 protein
Female
Humans
Immunohistochemistry
Immunotherapy
Laboratories
Lung cancer
Medicine
Metastasis
Mice
Mice, Nude
Monoclonal antibodies
Ostomy
Ovarian cancer
Pancreatic cancer
Patients
Receptor, ErbB-2 - metabolism
Salmonella
Salmonella Typhimurium
Salmonella typhimurium - physiology
Stromal cells
Surgery
Targeted cancer therapy
Transplantation, Heterologous
Transplants & implants
Trastuzumab
Trastuzumab - therapeutic use
Tumor cells
Tumors
University graduates
Uterine Cervical Neoplasms - drug therapy
Uterine Cervical Neoplasms - metabolism
Uterine Cervical Neoplasms - pathology
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Summary:We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0120358