Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model
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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.
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