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
AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
AntiCancer, Inc., San Diego, California, United States of America.
PLoS One. 2015 Jun 5;10(6):e0120358. doi: 10.1371/journal.pone.0120358. eCollection 2015.
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.
我们之前已经建立了HER-2阳性宫颈癌的小鼠模型。裸鼠体内的肿瘤具有与原发肿瘤相似的组织结构，并且用抗HER-2抗体染色时呈现出与患者癌症相同的模式。我们之前还开发了肿瘤靶向性鼠伤寒沙门氏菌A1-R，并已证明其对患者来源的肿瘤小鼠模型单独使用或联合使用时均有效。在当前研究中，我们确定了鼠伤寒沙门氏菌A1-R与曲妥珠单抗联合使用对HER-2阳性宫颈癌患者癌裸鼠模型的疗效。将小鼠随机分为5组并进行如下治疗：（1）不治疗；（2）卡铂（30mg/kg，腹腔注射，每周一次，共5周）；（3）曲妥珠单抗（20mg/kg，腹腔注射，每周一次，共5周）；（4）鼠伤寒沙门氏菌A1-R（5×10⁷CFU/只，腹腔注射，每周一次，共5周）；（5）鼠伤寒沙门氏菌A1-R（5×10⁷CFU/只，腹腔注射，每周一次，共5周）+曲妥珠单抗（20mg/kg，腹腔注射，每周一次，共5周）。与未治疗的小鼠相比，所有治疗方案均具有显著疗效。与单独使用曲妥珠单抗（p = 0.007）和单独使用鼠伤寒沙门氏菌A1-R（p = 0.039）相比，鼠伤寒沙门氏菌A1-R+曲妥珠单抗治疗的小鼠的相对肿瘤体积更小。与未治疗组相比，除了卡铂治疗的小鼠（p = 0.021）外，未发现明显的体重减轻。组织学检查显示，在用鼠伤寒沙门氏菌A1-R+曲妥珠单抗治疗的肿瘤中未检测到存活的肿瘤细胞，取而代之的是基质细胞。本研究结果表明，鼠伤寒沙门氏菌A1-R和曲妥珠单抗联合使用对HER-2表达的宫颈癌具有高效性。
