Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic

Kentaro Igarashi, Kei Kawaguchi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Shukuan Li, Qinghong Han, Yuying Tan, Ming Zhao, Yunfeng Li, Scott D. Nelson, Sarah M. Dry, Arun S. Singh, Irmina A. Elliott, Tara A. Russell, Mark A. Eckardt, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji MiwaHiroyuki Tsuchiya, Fritz C. Eilber, Robert M. Hoffman

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36 Citations (Scopus)

Abstract

In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G 2 , and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

Original languageEnglish
Pages (from-to)801-809
Number of pages9
JournalCell Cycle
Volume17
Issue number6
DOIs
Publication statusPublished - 2018 Mar 19
Externally publishedYes

Keywords

  • PDOX
  • Salmonella typhimurium A1-R
  • cisplatinum
  • decoy
  • kill
  • lung
  • metastasis
  • methioninase
  • osteosarcoma
  • resistance
  • trap

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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