Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model
- 116 Downloads
Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model.
Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week.
Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively).
Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.
KeywordsCervical cancer S. typhimurium A1-R Patient-derived orthotopic xenograft Nude mice Bacterial therapy
This paper is dedicated to the memory of A. R. Moossa, M.D., Sun Lee, M.D and Professor Li Jiaxi.
KM: Project development, data collection, data analysis, manuscript writing; TM, TM, MZ, TK, KK, KI, MM, TML, CH, SK, TK: data collection, data analysis; MB, KS, SRS, IE: data analysis; SRS : data analysis, manuscript writing and revision; RMH project development, data collection, data analysis, manuscript writing.
Compliance with ethical standards
Conflict of interest
KM, TK, KK, KI, MM and RMH are or were unsalaried associates of AntiCancer, Inc. MZ is an employee of AntiCancer Inc.. CH, SK and TK are unsalaried associates of AntiCancer Japan. AntiCancer Inc. and AntiCancer Japan use PDOX models for contract reserach. There are no other competing commercial interests.
All animal studies were conducted in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1. For patient studies, an informed consent was obtained, and PDOX studies were approved by the Institutional Ethics Committee of Kawasaki Medical School.
- 8.Boardman CH, Brady WE, Dizon DS, Kunos CA, Moore KN, Zanotti KM, Matthews C, Cosin JA, Aghajanian C, Fracasso PM (2018) A phase I evaluation of extended field radiation therapy with concomitant cisplatin chemotherapy followed by paclitaxel and carboplatin chemotherapy in women with cervical carcinoma metastatic to the para-aortic lymph nodes: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. https://doi.org/10.1016/j.ygyno.2018.08.006 Google Scholar
- 10.Fu X, Le P, Hoffman RM (1993) A metastatic-orthotopic transplant nude mouse model of human patient breast cancer. Anticancer Res 13:901–904Google Scholar
- 11.Fu X, Hoffman RM (1993) Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res 13:283–286Google Scholar
- 21.Kawaguchi K, Igarashi K, Murakami T et al (2017) Salmonella typhimurium A1-R targeting of a chemotherapy resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozlomide. Cell Cycle 16:1288–1294CrossRefGoogle Scholar
- 23.Murakami T, DeLong J, Eilber FC et al (2016) Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft PDOX model. Oncotarget 7:12783–12790Google Scholar
- 25.Igarashi K, Kawaguchi K, Kiyuna T et al (2017) Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:75874–75880Google Scholar
- 30.Hoffman RM (2016) Bacterial therapy of cancer: methods and protocols. In: Walker JM (ed) Methods in molecular biology 1409. Humana Press, New YorkGoogle Scholar
- 37.Nagakura C, Hayashi K, Zhao M, Yamauchi K (2009) Efficacy of a genetically-modified Salmonella typhimurium in an orthotopic human pancreatic cancer in nude mice. Anticancer Res 29:1873–1878Google Scholar
- 44.Kawaguchi K, Miyake K, Zhao M, Kiyuna T, Igarashi K, Miyake M, Higuchi T, Oshiro H, Bouvet M, Unno M, Hoffman RM (2018) Tumor targeting Salmonella typhimurium A1-R in combination with gemcitabine (GEM) regresses partially GEM-resistant pancreatic cancer patient-derived orthotopic xenograft (PDOX) nude mouse models. Cell Cycle 17(16):2019–2026CrossRefGoogle Scholar