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Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

Kentaro IgarashiAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA;Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

http://orcid.org/0000-0002-4680-4317

Kei KawaguchiAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Takashi MurakamiAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Tasuku KiyunaAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Kentaro MiyakeAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Scott D. NelsonDepartment of Pathology, University of California Los Angeles, CA, USA

Sarah M. DryDepartment of Pathology, University of California Los Angeles, CA, USA

Yunfeng LiDepartment of Pathology, University of California Los Angeles, CA, USA

Jane YanagawaDivision of Surgical Oncology, University of California, Los Angeles, CA, USA

Tara A. RussellDivision of Surgical Oncology, University of California, Los Angeles, CA, USA

http://orcid.org/0000-0002-3912-3601

Arun S. SinghDivision of Hematology-Oncology, University of California, Los Angeles, CA, USA

Norio YamamotoDepartment of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

Katsuhiro HayashiDepartment of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

Hiroaki KimuraDepartment of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

Shinji MiwaDepartment of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

Hiroyuki TsuchiyaDepartment of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan

Fritz C. EilberDivision of Surgical Oncology, University of California, Los Angeles, CA, USACorrespondence[email protected]

http://orcid.org/0000-0003-3336-9333

Robert M. HoffmanAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USACorrespondence[email protected]

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Figures & data

Figure 1. Distribution of fluorescence imaging. (A) S. typhimurium-A1-R-GFP targeting the osteosarcoma PDOX after intra-arterial (i.a.) injection. (B) S. typhimurium A1-R-GFP targeting the osteosarcoma after intravenous (i.v.) injection. Confocal microscopy imaging with the Olympus FV1000 demonstrated S. typhimurium A1-R-GFP targeting the osteosarcoma PDOX. Scale bars: 12.5 µm.

Figure 2. (A) Fluorescence intensity of S. typhimurium A1-R-GFP targeting the osteosarcoma PDOX after i.a. or i.v. administration. (B) Fluorescent area of S. typhimurium A1-R-GFP targeting the osteosarcoma PDOX after i.a. or i.v. administration.

Figure 3. (A) Treatment schema. Mice were treated with CDDP, S. typhimurium A1-R i.v. or S. typhimurium A1-R i.a. CDDP (6 mg/kg/week i.p. for 2 weeks); S. typhimurium A1-R i.v. (5 × 10⁷ CFU/100 μl, i.v., weekly, for 2 weeks); S. typhimurium A1-R i.a. (5 × 10⁵ CFU/100 μl, i.a., once). Tumor volume was measured at the indicated time points after the onset of treatment. n = 8mice/group. (B) Treatment efficacy. *p < 0.05, **p < 0.001.

Figure 4. Body weight after various treatments. Bar graphs show body weight in each group at pre-treatment and 2 weeks after drug administration.

Figure 5. Tumor histology. Hematoxylin and eosin (H&E)-stained section of the (A) original patient tumor; (B) untreated PDOX tumor; (C) PDOX tumor treated with CDDP; (D) PDOX tumor treated with S. typhimurium A1-R i.v.; and (E) PDOX tumor treated with S. typhimurium A1-R i.a.. Necrotic areas are indicated by yellow arrows. White scale bars: 80 µm.

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Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

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Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

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