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

  • Kentaro Miyake
  • Takuya MurataEmail author
  • Takashi Murakami
  • Ming Zhao
  • Tasuku Kiyuna
  • Kei Kawaguchi
  • Kentaro Igarashi
  • Masuyo Miyake
  • Thinzar M. Lwin
  • Chihiro Hozumi
  • Shin Komatsu
  • Takashi Kikuchi
  • Michael BouvetEmail author
  • Koichiro Shimoya
  • Shree Ram SinghEmail author
  • Itaru EndoEmail author
  • Robert M. HoffmanEmail author
Gynecologic Oncology
  • 73 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.

Keywords

Cervical cancer S. typhimurium A1-R Patient-derived orthotopic xenograft Nude mice Bacterial therapy 

Notes

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, M.D., Sun Lee, M.D and Professor Li Jiaxi.

Author contributions

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.

Ethical approval

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.AntiCancer Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Gastroenterological SurgeryYokohama City University Graduate School of MedicineYokohamaJapan
  4. 4.Department of Obstetrics and GynecologyKawasaki Medical SchoolOkayamaJapan
  5. 5.AntiCancer Japan Inc.NaritaJapan
  6. 6.Basic Research LaboratoryNational Cancer InstituteFrederickUSA

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