Author: Hozumi, Chihiro ; Hamada, Kazuyuki ; Tsunoda, Takuya ; Zhao, Ming ; Aoki, Yusuke ; Hoffman, Robert M ; Murata, Takuya ; Yamamoto, Jun ; Sugisawa, Norihiko ; Bouvet, Michael

BACKGROUND/AIMTriple-negative matrix-producing breast carcinoma (MPBC) is rare, recalcitrant, and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting leucine-arginine auxotroph Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model.MATERIALS AND METHODSThe PDOX MPBC model was established in the left second mammary gland of nude mice by surgical orthotopic implantation (SOI). PDOX models were randomized into two groups when the tumor volume reached over 70 mm³: a control group (n=6); and a tumor-targeting S. typhimurium A1-R group (n=7), [intravenous (i.v.) injection of S. typhimurium A1-R via the tail vein, weekly, for two weeks]. All mice were sacrificed on day 14. Tumor volume and body weight were measured once per week.RESULTSS. typhimurium A1-R exquisitely targeted and arrested the growth of the MPBC PDOX compared to the control group (p=0.017).CONCLUSIONS. typhimurium A1-R has future clinical potential for triple-negative MPBC patients.

01 May 2020·Anticancer ResearchQ4 · MEDICINE

Recombinant Methioninase Combined With Tumor-targeting Salmonella typhimurium A1-R Induced Regression in a PDOX Mouse Model of Doxorubicin-resistant Dedifferentiated Liposarcoma

Q4 · MEDICINE

Article

Author: Miyake, Kentaro ; Hoffman, Robert M ; Miwa, Shinji ; Kawaguchi, Kei ; Higuchi, Takashi ; Singh, Shree Ram ; Igarashi, Kentaro ; Dry, Sarah M ; Tsuchiya, Hiroyuki ; Kiyuna, Tasuku ; Nelson, Scott D ; Han, Qinghong ; Li, Yunfeng ; Kimura, Hiroaki ; Zhao, Ming ; Yamamoto, Norio ; Tan, Yuying ; Hayashi, Katsuhiro

BACKGROUND/AIMDedifferentiated liposarcoma (DDLPS) is associated with a poor survival rate even with multi-modality treatment. In the present study, we evaluated the efficacy of recombinant methioninase (rMETase) combined with tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R against a doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) mouse model.MATERIALS AND METHODSA recurrent high-grade DDLPS from the right retroperitoneum of a patient was grown orthotopically in the retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomly divided into the following groups: Control, no treatment; doxorubicin monotherapy; rMETase monotherapy; S. typhimurium A1-R monotherapy; S. typhimurium A1-R and rMETase combination therapy. Tumor length and width were measured before and after treatment.RESULTSOn day 14 after treatment, all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control except for doxorubicin monotherapy. rMETase combined with S. typhimurium A1-R was significantly more effective and regressed tumor volume compared to either rMETase or S. typhimurium A1-R alone. The relative body weight did not significantly differ between days 0 and 14 for individual groups.CONCLUSIONThe combination of rMETase and S. typhimurium A1-R has important clinical potential for this recalcitrant sarcoma.

01 Feb 2020·Translational OncologyQ3 · MEDICINE

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model

Q3 · MEDICINE

ArticleOA

Author: Dry, Sarah M ; Li, Yunfeng ; Miwa, Shinji ; Kawaguchi, Kei ; Kimura, Hiroaki ; Tsuchiya, Hiroyuki ; Kiyuna, Tasuku ; Nelson, Scott D ; Miyake, Masuyo ; Miyake, Kentaro ; Higuchi, Takashi ; Singh, Shree Ram ; Igarashi, Kentaro ; Hayashi, Katsuhiro ; Hoffman, Robert M ; Zhao, Ming ; Yamamoto, Norio

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC₅₀ value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

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