396 results on '"Kiyuna, Tasuku"'
Search Results
2. 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.
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Igarashi, Kentaro, Kawaguchi, Kei, Zhao, Ming, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Higuchi, Takashi, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M
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Oncology & Carcinogenesis ,Biochemistry and Cell Biology ,Clinical Sciences ,Oncology and Carcinogenesis - Abstract
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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- 2020
3. Eribulin Regresses a Doxorubicin-resistant Dedifferentiated Liposarcoma in a Patient-derived Orthotopic Xenograft Mouse Model
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IGARASHI, KENTARO, KAWAGUCHI, KEI, KIYUNA, TASUKU, MIYAKE, KENTARO, HIGUCHI, TAKASHI, YAMAMOTO, NORIO, HAYASHI, KATSUHIRO, KIMURA, HIROAKI, MIWA, SHINJI, SINGH, SHREE RAM, TSUCHIYA, HIROYUKI, and HOFFMAN, ROBERT M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Good Health and Well Being ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Dedifferentiation ,Cell Proliferation ,Deoxycytidine ,Docetaxel ,Doxorubicin ,Drug Resistance ,Neoplasm ,Furans ,Humans ,Indazoles ,Ketones ,Liposarcoma ,Male ,Mice ,Mice ,Nude ,Piperazines ,Pyridines ,Pyrimidines ,Sulfonamides ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,Gemcitabine ,Patient-derived orthotopic xenograft ,PDOX ,eribulin ,regression ,doxorubicin resistance ,dedifferentiated liposarcoma ,Immunology ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Background/aimDedifferentiated liposarcoma (DDLPS) is recalcitrant type of sarcoma. DDLPS has a low survival rate with high recurrence and metastasis. In the present study, we evaluated the efficacy of several drugs against doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model for precision oncology. To establish the PDOX model, a tumor from a patient who had recurrent high-grade DDLPS from the retroperitoneum was previously grown orthotopically in the retroperitoneum of nude mice.Materials and methodsWe randomized DDLPS PDOX models into 8 treatment groups when tumor volume became approximately 100 mm3: control, no treatment; G2, doxorubicin (DOX); G3, pazopanib (PAZ); G4, gemcitabine (GEM) combined with docetaxel (DOC); G5, trabectedin (YON); G6, temozolomide (TEM); G7, palbociclib (PAL); G8, eribulin (ERB). Tumor length and width were measured both at the beginning and at the end of treatment.ResultsAt the end of treatment (day 14), all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control, except DOX. ERB was significantly more effective and regressed tumor volume compared to other treatments on day 14 after initiation of treatment. No significant differences were found in the relative body weight on day 14 compared to day 0 in any group.ConclusionThe clinical potential of ERB against DDLPS is herein presented in a PDOX model.
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- 2020
4. A novel patient-derived orthotopic xenograft (PDOX) mouse model of highly-aggressive liver metastasis for identification of candidate effective drug-combinations
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Zhang, Zhiying, Hu, Kaiwen, Miyake, Kentaro, Kiyuna, Tasuku, Oshiro, Hiromichi, Wangsiricharoen, Sintawat, Kawaguchi, Kei, Higuchi, Takashi, Razmjooei, Sahar, Miyake, Masuyo, Chawla, Sant P, Singh, Shree Ram, and Hoffman, Robert M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,Colo-Rectal Cancer ,Cancer ,Liver Disease ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Benzimidazoles ,Bevacizumab ,Body Weight ,Colonic Neoplasms ,Fluorouracil ,Humans ,Irinotecan ,Liver Neoplasms ,Experimental ,Mice ,Nude ,Phenylurea Compounds ,Proof of Concept Study ,Pyridines ,Xenograft Model Antitumor Assays - Abstract
Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU) + irinotecan (IRI) + bevacizumab (BEV) and regorafenib (REG) + selumetinib (SEL) had significantly inhibited liver metastasis growth (p = 0.013 and p = 0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.
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- 2020
5. Prospective randomized study on the effect of disinfectants on suture contamination in arthroscopic rotator cuff repair
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Kamijo, Hideki, primary, Takahashi, Norimasa, additional, Matsuki, Keisuke, additional, Sasaki, Yuu, additional, Ueda, Yusuke, additional, Hoshika, Shota, additional, Matsuba, Tomoyuki, additional, Kiyuna, Tasuku, additional, Tamaki, Tomoshige, additional, and Haraguchi, Ryo, additional
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- 2024
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6. Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model.
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Miyake, Kentaro, Murata, Takuya, Murakami, Takashi, Zhao, Ming, Kiyuna, Tasuku, Kawaguchi, Kei, Igarashi, Kentaro, Miyake, Masuyo, Lwin, Thinzar, Hozumi, Chihiro, Komatsu, Shin, Kikuchi, Takashi, Shimoya, Koichiro, Singh, Shree, Endo, Itaru, Bouvet, Michael, and Hoffman, Robert
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Bacterial therapy ,Cervical cancer ,Nude mice ,Patient-derived orthotopic xenograft ,S. typhimurium A1-R ,Albumins ,Animals ,Disease Models ,Animal ,Doxorubicin ,Female ,Humans ,Mice ,Mice ,Nude ,Oligopeptides ,Paclitaxel ,Salmonella typhimurium ,Uterine Cervical Neoplasms ,Xenograft Model Antitumor Assays - 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
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- 2019
7. Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model
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Kiyuna, Tasuku, Tome, Yasunori, Murakami, Takashi, Kawaguchi, Kei, Igarashi, Kentaro, Miyake, Kentaro, Miyake, Masuyo, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Singh, Arun S, Russell, Tara A, Elliott, Irmina, Singh, Shree Ram, Kanaya, Fuminori, Eilber, Fritz C, and Hoffman, Robert M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Cardiovascular ,Aged ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Dioxoles ,Doxorubicin ,Drug Resistance ,Neoplasm ,Humans ,Liposarcoma ,Male ,Mice ,Neoplasm Recurrence ,Local ,Receptor ,Platelet-Derived Growth Factor alpha ,Tetrahydroisoquinolines ,Trabectedin ,Xenograft Model Antitumor Assays ,Patient-derived orthotopic xenograft ,PDOX ,PDGFRA amplification ,Precision medicine ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Epidemiology - Abstract
BackgroundPleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS.MethodsWe used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight.ResultsThe PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p
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- 2018
8. Tumor‐targeting Salmonella typhimurium A1‐R arrests a doxorubicin‐resistant PDGFRA‐amplified patient‐derived orthotopic xenograft mouse model of pleomorphic liposarcoma
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Kiyuna, Tasuku, Tome, Yasunori, Murakami, Takashi, Zhao, Ming, Miyake, Kentaro, Igarashi, Kentaro, Kawaguchi, Kei, Miyake, Masuyo, Oshiro, Hiromichi, Higuchi, Takashi, Li, Yunfeng, Dry, Sarah M, Nelson, Scott D, Russell, Tara A, Eckardt, Mark A, Singh, Arun S, Kanaya, Fuminori, Eilber, Fritz C, and Hoffman, Robert M
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Cancer ,Aged ,Animals ,Body Weight ,Combined Modality Therapy ,Doxorubicin ,Drug Resistance ,Neoplasm ,Gene Amplification ,Green Fluorescent Proteins ,Humans ,Liposarcoma ,Male ,Mice ,Random Allocation ,Receptor ,Platelet-Derived Growth Factor alpha ,Salmonella typhimurium ,Sarcoma ,Treatment Outcome ,Xenograft Model Antitumor Assays ,green fluorescent protein ,patient-derived orthotopic xenograft ,PDGFRA amplification ,pleomorphic liposarcoma ,Salmonella typhimurium A1-R ,soft-tissue sarcoma ,tumor targeting ,Biochemistry and Cell Biology ,Medical Physiology ,Biochemistry & Molecular Biology - Abstract
Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.
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- 2018
9. Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations.
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Miyake, Kentaro, Kawaguchi, Kei, Miyake, Masuyo, Zhao, Ming, Kiyuna, Tasuku, Igarashi, Kentaro, Zhang, Zhiying, Murakami, Takashi, Li, Yunfeng, Nelson, Scott D, Bouvet, Michael, Elliott, Irmina, Russell, Tara A, Singh, Arun S, Hiroshima, Yukihiko, Momiyama, Masashi, Matsuyama, Ryusei, Chishima, Takashi, Singh, Shree Ram, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Biochemistry ,Cancer research ,Genetics ,Microbiology - Abstract
Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration [p.o.], daily, for 3 weeks); G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease.
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- 2018
10. Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model.
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Igarashi, Kentaro, Kawaguchi, Kei, Li, Shukuan, Han, Qinghong, Tan, Yuying, Gainor, Emily, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Higuchi, Takashi, Oshiro, Hiromichi, Singh, Arun S, Eckardt, Mark A, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
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PDOX ,doxorubicin ,patient-derived orthotopic xenograft ,recombinant methioninase ,synovial sarcoma ,Oncology and Carcinogenesis - Abstract
Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease.
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- 2018
11. Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer
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Kawaguchi, Kei, Miyake, Kentaro, Han, Qinghong, Li, Shukuan, Tan, Yuying, Igarashi, Kentaro, Lwin, Thinzar M, Higuchi, Takashi, Kiyuna, Tasuku, Miyake, Masuyo, Oshiro, Hiromichi, Bouvet, Michael, Unno, Michiaki, and Hoffman, Robert M
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Biochemistry and Cell Biology ,Biological Sciences ,Orphan Drug ,Cancer ,Digestive Diseases ,Pancreatic Cancer ,Rare Diseases ,Animals ,Antimetabolites ,Antineoplastic ,Antineoplastic Combined Chemotherapy Protocols ,Carbon-Sulfur Lyases ,Deoxycytidine ,Drug Administration Schedule ,Drug Resistance ,Neoplasm ,Gene Expression ,Humans ,Injections ,Intraperitoneal ,Male ,Methionine ,Mice ,Mice ,Nude ,Molecular Targeted Therapy ,Pancreatic Neoplasms ,Recombinant Proteins ,Tumor Burden ,Xenograft Model Antitumor Assays ,Gemcitabine ,Recombinant methioninase ,methionine dependence ,pancreatic cancer ,patient-derived orthotopic xenograft ,nude mice ,orthotopic ,gemcitabine ,precision therapy ,Developmental Biology ,Biochemistry and cell biology - Abstract
Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.
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- 2018
12. Growth of doxorubicin‐resistant undifferentiated spindle‐cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase
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Igarashi, Kentaro, Li, Shukuan, Han, Qinghong, Tan, Yuying, Kawaguchi, Kei, Murakami, Takashi, Kiyuna, Tasuku, Miyake, Kentaro, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Singh, Arun S, Elliott, Irmina A, Russell, Tara A, Eckardt, Mark A, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
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Biotechnology ,Cancer ,Rare Diseases ,Orphan Drug ,Animals ,Carbon-Sulfur Lyases ,Deoxycytidine ,Disease Models ,Animal ,Docetaxel ,Doxorubicin ,Female ,Indazoles ,Melanoma ,Mice ,Mice ,Nude ,Pyrimidines ,Sarcoma ,Ewing ,Sulfonamides ,Taxoids ,Xenograft Model Antitumor Assays ,doxorubicin ,patient-derived orthotopic xenograft ,PDOX ,recombinant methioninase ,resistant ,undifferentiated spindle-cell sarcoma ,Gemcitabine ,Biochemistry and Cell Biology ,Medical Physiology ,Biochemistry & Molecular Biology - Abstract
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.
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- 2018
13. 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
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Igarashi, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Li, Shukuan, Han, Qinghong, Tan, Yuying, Zhao, Ming, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Singh, Arun S, Elliott, Irmina A, Russell, Tara A, Eckardt, Mark A, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
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Rare Diseases ,Cancer ,Animals ,Antineoplastic Agents ,Carbon-Sulfur Lyases ,Cisplatin ,Disease Models ,Animal ,Drug Resistance ,Neoplasm ,Drug Therapy ,Combination ,G2 Phase Cell Cycle Checkpoints ,Humans ,Lung Neoplasms ,Mice ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Osteosarcoma ,Recombinant Proteins ,S Phase Cell Cycle Checkpoints ,Salmonella typhimurium ,Transplantation ,Heterologous ,Tumor Cells ,Cultured ,osteosarcoma ,metastasis ,lung ,PDOX ,resistance ,Salmonella typhimurium A1R ,decoy ,methioninase ,trap ,cisplatinum ,kill ,Salmonella typhimurium A1-R ,Biochemistry and Cell Biology ,Developmental Biology - 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/G2, 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 × 107 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 107 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 × 107 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.
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- 2018
14. Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients
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Kawaguchi, Kei, Igarashi, Kentaro, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Murakami, Takashi, Chmielowski, Bartosz, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Singh, Arun S, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
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Cancer ,Rare Diseases ,Orphan Drug ,Good Health and Well Being ,Aged ,Animals ,Antibiotics ,Antineoplastic ,Body Weight ,Cell Line ,Tumor ,Disease Models ,Animal ,Doxorubicin ,Female ,Humans ,Male ,Mice ,Mice ,Nude ,Middle Aged ,Muscle Neoplasms ,Precision Medicine ,Sarcoma ,Transplantation ,Heterologous ,Soft tissue sarcoma ,undifferentiated/unclassified soft tissue sarcoma ,PDOX ,nude mice ,drug-response ,doxorubicin ,precision therapy ,individualized therapy ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Doxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control; and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p = 0.0054, p = 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivo study to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS.
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- 2018
15. Intra-tumor L-methionine level highly correlates with tumor size in both pancreatic cancer and melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse models
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Kawaguchi, Kei, Han, Qinghong, Li, Shukuan, Tan, Yuying, Igarashi, Kentaro, Miyake, Kentaro, Kiyuna, Tasuku, Miyake, Masuyo, Chemielwski, Bartosz, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Singh, Arun S, Eckardt, Mark A, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Rare Diseases ,Digestive Diseases ,Pancreatic Cancer ,melanoma ,methionine dependence ,pancreatic cancer ,recombinant methionine ,tumor methionine ,Oncology and carcinogenesis - Abstract
An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3, the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX (p
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- 2018
16. Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention
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Kawaguchi, Kei, Han, Qinghong, Li, Shukuan, Tan, Yuying, Igarashi, Kentaro, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Chmielowski, Bartosz, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Singh, Arun S, Eckardt, Mark A, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Brain Disorders ,Prevention ,Cancer ,Administration ,Oral ,Aged ,Animals ,Carbon-Sulfur Lyases ,Female ,Humans ,Melanoma ,Mice ,Nude ,Mutation ,Proto-Oncogene Proteins B-raf ,Recombinant Proteins ,Xenograft Model Antitumor Assays ,Recombinant methioninase ,methionine dependence ,oral administration ,pyridoxal-L-phosphate ,melanoma ,PDOX ,nude mice ,orthotopic ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
The elevated methionine (MET) use by cancer cells is termed MET dependence and may be the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo. We previously reported that rMETase, administrated by intra-peritoneal injection (ip-rMETase), could inhibit tumor growth in a patient-derived orthotopic xenograft (PDOX) model of a BRAF-V600E mutant melanoma. In the present study, we compared ip-rMETase and oral rMETase (o-rMETase) for efficacy on the melanoma PDOX. Melanoma PDOX nude mice were randomized into four groups of 5 mice each: untreated control; ip-rMETase (100 units, i.p., 14 consecutive days); o-rMETase (100 units, p.o., 14 consecutive days); o-rMETase+ip-rMETase (100 units, p.o.+100 units, i.p., 14 consecutive days). All treatments inhibited tumor growth on day 14 after treatment initiation, compared to untreated control (ip-rMETase, p
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- 2018
17. Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model
- Author
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Igarashi, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Singh, Arun S, Elliott, Irmina A, Russell, Tara A, Eckardt, Mark A, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Pediatric ,PDOX ,irinotecan ,nude mice ,osteosarcoma ,temozolomide ,Oncology and carcinogenesis - Abstract
Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP)-resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX.
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- 2018
18. Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models
- Author
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Kawaguchi, Kei, Igarashi, Kentaro, Li, Shukuan, Han, Qinghong, Tan, Yuying, Miyake, Kentaro, Kiyuna, Tasuku, Miyake, Masuyo, Murakami, Takashi, Chmielowski, Bartosz, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Cancer ,melanoma ,recombinant methioninase ,methionine dependence ,BRAF-V600E mutation ,PDOX ,Oncology and carcinogenesis - Abstract
Melanoma is a recalcitrant disease. Melanoma patients with the BRAF-V600E mutation have been treated with the drug vemurafenib (VEM) which targets this mutation. However, we previously showed that VEM is not very effective against a BRAF-V600E melanoma mutant in a patient-derived orthotopic xenograft (PDOX) model. In contrast, we demonstrated that recombinant methioninase (rMETase) which targets the general metabolic defect in cancer of methionine dependence, was effective against the BRAF-V600E mutant melanoma PDOX model. In the present study, we demonstrate that rMETase is effective against a BRAF-V600E-negative melanoma PDOX which we established. Forty BRAF-V600E-negative melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); temozolomide (TEM) (25 mg/kg, p.o., 14 consecutive days, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); TEM + rMETase (TEM: 25 mg/kg, p.o., rMETase: 100 units, i.p., 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0003, rMETase: p = 0.0006, TEM/rMETase: p = 0.0002) on day 14 after initiation. Combination therapy of TEM and rMETase was significantly more effective than either mono-therapy (TEM: p = 0.0113, rMETase: p = 0.0173). The present study shows that TEM combined with rMETase is effective for BRAF-V600E-negative melanoma PDOX similar to the BRAF-V600E-positive mutation melanoma. These results suggest rMETase in combination with first-line chemotherapy can be highly effective in both BRAF-V600E-negative as well as BRAF-V600E-positive melanoma and has clinical potential for this recalcitrant disease.
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- 2018
19. Regorafenib regresses an imatinib-resistant recurrent gastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit in a patient-derived orthotopic xenograft (PDOX) nude mouse model.
- Author
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Miyake, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Miyake, Masuyo, Igarashi, Kentaro, Zhang, Zhiying, Murakami, Takashi, Li, Yunfeng, Nelson, Scott D, Elliott, Irmina, Russell, Tara, Singh, Arun, Hiroshima, Yukihiko, Momiyama, Masashi, Matsuyama, Ryusei, Chishima, Takashi, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Tumor Cells ,Cultured ,Animals ,Humans ,Mice ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Gastrointestinal Stromal Tumors ,Disease Models ,Animal ,Body Weight ,Phenylurea Compounds ,Pyridines ,Antineoplastic Agents ,Transplantation ,Heterologous ,Drug Resistance ,Neoplasm ,Mutation ,Exons ,Male ,Proto-Oncogene Proteins c-kit ,Imatinib Mesylate ,GIST ,Gleevec ,imatinib ,nude mice ,patient-derived orthotopic xenograft ,regorafenib ,Rare Diseases ,Orphan Drug ,Digestive Diseases ,Cancer ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Gastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit is a rare type of sarcoma. The aim of this study was to determine drug sensitivity for a regionally-recurrent case of GIST using a patient-derived orthotopic xenograft (PDOX) model. The PDOX model was established in the anterior wall of the stomach. GIST PDOX models were randomized into 5 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration (p.o.), daily, for 3 weeks); G3, sunitinib group (p.o., daily, for 3 weeks); G4, regorafenib (p.o., daily, for 3 weeks); G5, pazopanib (p.o., daily, for 3 weeks). All mice were sacrificed on day 22. Tumor volume was evaluated on day 0 and day 22 by laparotomy. Body weight were measured 2 times per week. Though regorafenib is third-line therapy for GIST, it was the most effective drug and regressed the tumor significantly (p < 0.001). Sunitinib suppressed tumor growth compared to the control group (p = 0.002). Imatinib, first-line therapy for GIST, and pazopanib did not have significant efficacy compared to the control group (p = 0.886, p = 0.766). The implications of this result is discussed for GIST patients.
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- 2018
20. Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy, and tumor-targeting S. typhimurium A1-R is superior to first-line chemotherapy.
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Miyake, Kentaro, Kiyuna, Tasuku, Miyake, Masuyo, Kawaguchi, Kei, Yoon, Sang Nam, Zhang, Zhiying, Igarashi, Kentaro, Razmjooei, Sahar, Wangsiricharoen, Sintawat, Murakami, Takashi, Li, Yunfeng, Nelson, Scott D, Russell, Tara A, Singh, Arun S, Hiroshima, Yukihiko, Momiyama, Masashi, Matsuyama, Ryusei, Chishima, Takashi, Singh, Shree Ram, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
- Abstract
Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy.
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- 2018
21. The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.
- Author
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Miyake, Kentaro, Murakami, Takashi, Kiyuna, Tasuku, Igarashi, Kentaro, Kawaguchi, Kei, Miyake, Masuyo, Li, Yunfeng, Nelson, Scott D, Dry, Sarah M, Bouvet, Michael, Elliott, Irmina A, Russell, Tara A, Singh, Arun S, Eckardt, Mark A, Hiroshima, Yukihiko, Momiyama, Masashi, Matsuyama, Ryusei, Chishima, Takashi, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Ewing’s sarcoma ,irinotecan ,patient-derived orthotopic xenograft ,temozolomide ,third-line chemotherapy ,Ewing's sarcoma ,Rare Diseases ,Orphan Drug ,Pediatric Cancer ,Pediatric ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Oncology and Carcinogenesis - Abstract
The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient.
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- 2017
22. Splenectomy is associated with an aggressive tumor growth pattern and altered host immunity in an orthotopic syngeneic murine pancreatic cancer model
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Hwang, Ho Kyoung, Murakami, Takashi, Kiyuna, Tasuku, Kim, Hoon, Lee, Sung Hwan, Kang, Chang Moo, Hoffman, Robert M, and Bouvet, Michael
- Subjects
Digestive Diseases ,Cancer ,Pancreatic Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,pancreatic cancer ,orthotopic mouse models ,splenectomy ,tumor infiltrating lymphocytes ,metastases ,Oncology and Carcinogenesis - Abstract
The purpose of this study was to investigate whether splenectomy influences the tumor growth and metastatic pattern in an orthotopic syngeneic murine pancreatic cancer model. Murine pancreatic cancer cells (PAN02) were subcutaneously injected into the flanks of nude mice. A small tumor fragment (3 mm2), harvested from a subcutaneous tumor. was orthotopically implanted in the tail of the pancreas of C57/BL6 mice without splenectomy (control group, n=15) or with simultaneous splenectomy (splenectomy group, n=15). Tumor growth and metastatic patterns were analyzed by laparotomy at 21 days after surgery. No tumor growth was found in 5 mice (33.3%) of the control group and 1 mouse (6.7%) of the splenectomy group (p=0.169). Tumor volume was significantly larger in splenectomy group (p=0.013). Peritoneal seeding was more frequently observed in the splenectomy group (11 (73.3%) vs. 4 (26.7%), p=0.011). There were no differences in the number of liver and kidney metastasis between the two groups. The ratios of tumor-infiltrating CD4+ to FoxP3+ and CD8+ to FoxP3+ were significantly higher in the control group compared to the splenectomy group (8.2 ± 9.3 vs. 2.4 ± 1.5, p=0.046; 2.5 ± 1.4 vs. 1.5 ± 0.4, p=0.031, respectively). Splenectomy enhanced tumor growth and peritoneal seeding in an orthotopic syngeneic murine pancreatic cancer mouse model. The ramification of these results are discussed for pancreatic cancer treatment.
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- 2017
23. Analysis of Stroma Labeling During Multiple Passage of a Sarcoma Imageable Patient‐Derived Orthotopic Xenograft (iPDOX) in Red Fluorescent Protein Transgenic Nude Mice
- Author
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Kiyuna, Tasuku, Murakami, Takashi, Tome, Yasunori, Kawaguchi, Kei, Igarashi, Kentaro, Miyake, Kentaro, Kanaya, Fuminori, Singh, Arun, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Biotechnology ,Rare Diseases ,Animals ,Heterografts ,Humans ,Luminescent Proteins ,Mice ,Mice ,Nude ,Mice ,Transgenic ,Neoplasm Transplantation ,Optical Imaging ,Sarcoma ,Staining and Labeling ,SOFT TISSUE SARCOMA ,IMAGEABLE PATIENT-DERIVED ORTHOTOPIC XENOGRAFT ,RED FLUORESCENT PROTEIN ,TRANSGENIC RFP NUDE MOUSE ,PASSAGING ,STROMA LABELING ,IMAGING ,Medical Physiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
A patient-derived orthotopic xenograft (PDOX) model of undifferentiated pleomorphic sarcoma (UPS) was previously established that acquired red fluorescent protein (RFP)-expressing stroma by growth in an RFP transgenic nude mouse. In the present study, an imageable PDOX model (iPDOX) of UPS was established by orthotopic implantation in the biceps femoris of transgenic RFP nude mice. After the tumors grew to a diameter of 10 mm, they were harvested and the brightest portion of the tumors were subsequently orthotopically transplanted to both RFP and non-colored nude mice. The UPS PDOX tumor was again transplanted to RFP transgenic and non-colored nude mice, and finally a 3rd passage was made in the same manner. Five UPS tumors from each passage in both RFP and non-colored mouse models were harvested. The FV1,000 confocal microscope was used to visualize and quantitate the RFP area of the resected tumors. The average percent fluorescent area in the first passage of RFP mice was 34 ± 22%; in the second passage, 34 ± 20%; and 36 ± 11% in the third passage of RFP transgenic nude mice. The average tumor RFP area in the first passage from RFP mice to non-colored mice was 20 ± 7%; in the second passage, 28 ± 11%; in the third passage was 27 ± 13%. The present results demonstrate the extensive and stable acquisition of stroma by the UPS-tumor growing orthotopically in transgenic RFP nude mice (iPDOX). This model can be used for screening for effective drugs for individual patients and drug discovery. J. Cell. Biochem. 118: 3367-3371, 2017. © 2017 Wiley Periodicals, Inc.
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- 2017
24. Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model.
- Author
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Kawaguchi, Kei, Igarashi, Kentaro, Li, Shukuan, Han, Qinghong, Tan, Yuying, Kiyuna, Tasuku, Miyake, Kentaro, Murakami, Takashi, Chmielowski, Bartosz, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
melanoma ,metabolic targeting ,methionine dependence ,recombinant methioninase ,temozolomide ,Oncology and Carcinogenesis - Abstract
An excessive requirement for methionine termed methionine dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by methionine deprivation such as with recombinant methioninase (rMETase). The present study used a previously-established patient-derived orthotopic xenograft (PDOX) nude mouse model of BRAF V600E-mutant melanoma to determine the efficacy of rMETase in combination with a first-line melanoma drug, temozolomide (TEM). In the present study 40 melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n=10); TEM (25 mg/kg, oral 14 consecutive days, n=10); rMETase (100 units, intraperitoneal 14 consecutive days, n=10); combination TEM + rMETase (TEM: 25 mg/kg, oral rMETase: 100 units, intraperitoneal 14 consecutive days, n=10). All treatments inhibited tumor growth compared to untreated control (TEM: p=0.0081, rMETase: p=0.0037, TEM-rMETase: p=0.0024) on day 14 after initiation. However, the combination therapy of TEM and rMETase was significantly more efficacious than either mono-therapy (TEM: p=0.0051, rMETase: p=0.0051). The present study is the first demonstrating the efficacy of rMETase combination therapy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as melanoma, where rMETase may enhance first-line therapy.
- Published
- 2017
25. Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model
- Author
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Igarashi, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Murakami, Takashi, Miwa, Shinji, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Singh, Arun S, Kimura, Hiroaki, Hayashi, Katsuhiro, Yamamoto, Norio, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Pediatric ,Rare Diseases ,Orphan Drug ,Cancer ,rhabdomosarcoma ,nude mice ,patient-derived orthotopic xenograft ,temozolomide ,irinotecan ,combination ,Oncology and Carcinogenesis - Abstract
Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and recalcitrant, highly-malignant mesenchymal tumor in need of improved therapeutic strategies. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). We previously described the development of a PDOX model of adult pleomorphic RMS where the tumor behaved similar to the patient donor. A high-grade pleomorphic rhabdomyosarcoma from a striated muscle was previously grown orthotopically in the right biceps-femoris muscle of nude mice to establish the PDOX model. In the present study, the PDOX models were randomized into the following treatment groups when tumor volume reached 100 mm3: G1, control without treatment; G2, cyclophosphamide (CPA) 140 mg/kg, intraperitoneal (i.p.) injection, weekly, for 3 weeks; G3, temozolomide (TEM), 25 mg/kg, per oral (p.o.), daily, for 21 days; G4, temozolomide (TEM) 25 mg/kg, p.o., daily, for 21 days combined with irinotecan (IRN), 4 mg/kg, i.p., daily for 21 days. After 3 weeks, treatment of PDOX with TEM combined with IRN was so powerful that it resulted in tumor regression and the smallest tumor volume compared to other groups. The RMS PDOX model should be of use to design the treatment program for the patient and for drug discovery and evaluation for this recalcitrant tumor type.
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- 2017
26. A novel anionic phosphate platinum complex effectively targets an undifferentiated pleomorphic sarcoma better than cisplatinum and doxorubicin in a patient-derived orthotopic xenograft (PDOX)
- Author
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Igarashi, Kentaro, Kawaguchi, Kei, Murakami, Takashi, Kiyuna, Tasuku, Miyake, Kentaro, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Singh, Arun S, Miwa, Shinji, Odani, Akira, Eilber, Fritz C, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Orphan Drug ,Cancer ,Rare Diseases ,platinum complex ,3Pt ,undifferentiated pleomorphic sarcoma ,PDOX ,efficacy ,Oncology and Carcinogenesis - Abstract
A patient high-grade undifferentiated pleomorphic soft-tissue sarcoma (UPS) from a striated muscle was previously orthotopically implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) nude-mouse model. In the present study, two weeks after orthotopic transplantation of the UPS, mice were treated intraperitoneally with cisplatinum (CDDP), doxorubicin (DOX) or a novel anionic-phosphate-platinum compound 3Pt. Treatments were repeated weekly for a total of 3 times. Six weeks after transplantation, all mice were sacrificed and evaluated. After two weeks treatment, tumor sizes were as follows: control (G1): 2208.3 mm3; CDDP (G2): 841.8±3 mm3, p=0.0001; DOX (G3): 693.1±3 mm3, p=6.56E-7; 3Pt (G4): 333.7±1 mm3, p=4.8E-8. 3Pt showed significantly more efficacy compared to other therapy drugs tested: CDDP (p=0.0002), DOX (p=0.001). There were no animal deaths in any of the four groups. The present results suggest 3Pt is a promising new candidate for UPS since it was demonstrated to be effective in a PDOX model.
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- 2017
27. A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology
- Author
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Igarashi, Kentaro, Murakami, Takashi, Kawaguchi, Kei, Kiyuna, Tasuku, Miyake, Kentaro, Zhang, Yong, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Yanagawa, Jane, Russell, Tara A, Singh, Arun S, Tsuchiya, Hiroyuki, Elliott, Irmina, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Cancer ,Rare Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,osteosarcoma ,recurrence ,lung metastasis ,PDOX ,chemotherapy ,Oncology and Carcinogenesis - Abstract
In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor sizes and body weight were measured with calipers and a digital balance twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3, TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while precisely maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.
- Published
- 2017
28. Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide
- Author
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Kawaguchi, Kei, Igarashi, Kentaro, Murakami, Takashi, Kiyuna, Tasuku, Zhao, Ming, Zhang, Yong, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Singh, Arun S, Chmielowski, Bartosz, Li, Yunfeng, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
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Cancer ,Rare Diseases ,Aged ,Animals ,Antineoplastic Agents ,Dacarbazine ,Disease Models ,Animal ,Drug Administration Schedule ,Drug Resistance ,Neoplasm ,Female ,Heterografts ,Humans ,Indoles ,Melanoma ,Mice ,Mice ,Nude ,Microscopy ,Confocal ,Proto-Oncogene Proteins B-raf ,Salmonella typhimurium ,Sulfonamides ,Temozolomide ,Vemurafenib ,combination therapy ,drug-response ,melanoma ,nude mice ,orthotopic ,PDOX ,precision therapy ,Salmonella typhimurium A1-R ,temozolomide ,tumor regression ,vemurafenib ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with temozolomide (TEM) (25 mg/kg, p.o. for 14 consecutive days) combined with S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with vemurafenib (VEM) (30 mg/kg, p.o., for 14 consecutive days) combined with S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimurium A1-R: p < 0.01; TEM combined with S. typhimurium A1-R: p < 0.01; VEM combined with S. typhimurium A1-R: p < 0.01). Combination therapy with S. typhimurium A1-R was significantly more effective on tumor growth than S. typhimurium A1-R alone (with TEM: p < 0.01; with VEM: p < 0.01). Combination therapy significantly increased S. typhimurium A1-R tumor targeting alone (S. typhimurium A1-R + TEM: p < 0.01, S. typhimurium A1-R + VEM: p < 0.01), relative to S. typhimurium A1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimurium A1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.
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- 2017
29. MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX).
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Kawaguchi, Kei, Igarashi, Kentaro, Murakami, Takashi, Kiyuna, Tasuku, Lwin, Thinzar M, Hwang, Ho Kyoung, Delong, Jonathan C, Clary, Bryan M, Bouvet, Michael, Unno, Michiaki, and Hoffman, Robert M
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Pancreatic Neoplasms ,Disease Models ,Animal ,Azetidines ,Piperidines ,Pyridones ,Pyrimidinones ,Mitogen-Activated Protein Kinases ,Deoxycytidine ,Antineoplastic Agents ,Protein Kinase Inhibitors ,Xenograft Model Antitumor Assays ,Dose-Response Relationship ,Drug ,Drug Resistance ,Neoplasm ,PDOX ,drug-response ,nude mice ,orthotopic ,pancreatic cancer ,Cell Line ,Tumor ,Disease Models ,Animal ,Dose-Response Relationship ,Drug ,Drug Resistance ,Neoplasm ,Oncology and Carcinogenesis - Abstract
A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy.
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- 2017
30. The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.
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Murakami, Takashi, Kiyuna, Tasuku, Kawaguchi, Kei, Igarashi, Kentaro, Singh, Arun S, Hiroshima, Yukihiko, Zhang, Yong, Zhao, Ming, Miyake, Kentaro, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, DeLong, Jonathan C, Lwin, Thinzar M, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Doxorubicin ,Green Fluorescent Proteins ,Xenograft Model Antitumor Assays ,Middle Aged ,Female ,Sarcoma ,Ewing ,Ewing's sarcoma ,PDOX ,Salmonella typhimurium A1-R ,bacterial therapy of cancer ,patient-derived orthotopic xenograft ,Cancer ,Pediatric Cancer ,Rare Diseases ,Pediatric ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P < 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.
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- 2017
31. Combination of gemcitabine and docetaxel regresses both gastric leiomyosarcoma proliferation and invasion in an imageable patient-derived orthotopic xenograft (iPDOX) model.
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Kawaguchi, Kei, Igarashi, Kentaro, Murakami, Takashi, Kiyuna, Tasuku, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Russell, Tara A, Singh, Arun S, Chmielowski, Bartosz, Unno, Michiaki, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Mice ,Transgenic ,Humans ,Mice ,Nude ,Leiomyosarcoma ,Stomach Neoplasms ,Neoplasm Invasiveness ,Body Weight ,Taxoids ,Luminescent Proteins ,Deoxycytidine ,Antineoplastic Combined Chemotherapy Protocols ,Imaging ,Three-Dimensional ,Tumor Burden ,Xenograft Model Antitumor Assays ,Cell Proliferation ,Docetaxel ,Gemcitabine ,PDOX ,docetaxel ,drug-response ,gastric leiomyosarcoma ,gemcitabine ,nude mice ,orthotopic ,precision therapy ,red fluorescent protein ,tumor regression ,Cancer ,Clinical Research ,Orphan Drug ,Rare Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Gastric leiomyosarcoma is a recalcitrant cancer and the chemotherapy strategy is controversial. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of gastric leiomyosarcoma to identify an effective therapeutic regimen to develop individualized precision medicine for this disease. The gastric leiomyosarcoma obtained from a patient was first grown in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP) to stably label the tumor stroma. The RFP-expressing tumor was then passaged orthotopically in the gastric wall of non-transgenic nude mice to establish an imageable PDOX (iPDOX) model. The bright fluorescent tumor was readily imaged over time to determine drug efficacy. Four weeks after implantation, 70 PDOX nude mice were divided into 7 groups: control without treatment (n = 10); doxorubicin (DOX) (2.4 mg/kg, intraperitoneally (i.p.), once a week for 2 weeks, n = 10); gemcitabine (GEM)/ docetaxel (DOC) (GEM: 100 mg/kg, DOC: 20 mg/kg, i.p., once a week for 2 weeks, n = 10); cyclophosphamide (CPA) (140 mg/kg, i.p., once a week for 2 weeks, n = 10); temozolomide (TEM) (25 mg/kg, orally, daily for 14 consecutive days, n = 10); yondelis (YON) (0.15 mg/kg, i.v., once a week for 2 weeks, n = 10); pazopanib (PAZ) (100 mg/kg, orally, daily for 14 consecutive days, n = 10). On day 14 from initiation of treatment, all treatments except PAZ significantly inhibited tumor growth compared with untreated control (DOX: p < 0.01, GEM/DOC: p < 0.01, CPA: p < 0.01, TEM: p < 0.01, YON: p < 0.01) on day 14 after initiation. In addition, only GEM/DOC was more significantly effective than DOX (p < 0.05). GEM/DOC could regress the leimyosarcoma in the PDOX model and has important clinical potential for precision individual treatment of leiomyosarcoma patients.
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- 2017
32. 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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Igarashi, Kentaro, Kawaguchi, Kei, Murakami, Takashi, Kiyuna, Tasuku, Miyake, Kentaro, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Yanagawa, Jane, Russell, Tara A, Singh, Arun S, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Nude ,Salmonella typhimurium ,Osteosarcoma ,Bone Neoplasms ,Lung Neoplasms ,Cisplatin ,Tumor Burden ,Injections ,Intra-Arterial ,Xenograft Model Antitumor Assays ,Neoplasm Transplantation ,Drug Resistance ,Neoplasm ,Adolescent ,Heterografts ,PDOX ,Salmonella typhimurium A1-R ,cisplatinum-resistant ,intra-arterial ,recurrent ,Rare Diseases ,Orphan Drug ,Cancer ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Previously, a patient-derived orthotopic xenograft (PDOX) model was established with a lung metastasis from an osteosarcoma patient which developed after adjuvant cisplatinum (CDDP) treatment. In this model, we previously demonstrated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared with CDDP. In the present report, osteosarcoma tissue was implanted orthotopically in the distal femur of mice which were randomized into the following groups when tumor volume reached approximately 100 mm3; On day 14 after initiation of treatment, all but CDDP significantly inhibited tumor volume growth compared with untreated controls. Control (G1): 793.7 ± 215.0 mm3; CDDP (G2): 588.1 ± 176.9 mm3; Salmonella typhimurium A1-R (S. typhimurium A1-R) intravenous (i.v.) (G3): 269.7 ± 72.7 mm3; S. typhimurium A1-R intra-arterial (i.a.) (G4): 70.2 ± 18.9 mm3 (CDDP: p = 0.056; S. typhimurium A1-R i.v.: p = 0.0001; S. typhimurium A1-R i.a.: p = 0.00003, all vs. untreated controls). i.a. administration of S. typhimurium A1-R was significantly more effective than either CDDP (p = 0.00007), or i.v. administration of S. typhimurium A1-R (p = 0.00007) and significantly regressed the tumor volume compared with day 0 (p = 0.001). The new model of i.a. administration of S. typhimurium A1-R has great promise for the treatment of recalcitrant osteosarcoma.
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- 2017
33. Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model
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Murakami, Takashi, Hiroshima, Yukihiko, Miyake, Kentaro, Hwang, Ho Kyoung, Kiyuna, Tasuku, DeLong, Jonathan C, Lwin, Thinzar M, Matsuyama, Ryusei, Mori, Ryutaro, Kumamoto, Takafumi, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
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Digestive Diseases ,Rare Diseases ,Clinical Research ,Pancreatic Cancer ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Benzamides ,Cell Tracking ,Dioxoles ,Disease Models ,Animal ,Fluorescence ,Gene Expression Regulation ,Neoplastic ,Green Fluorescent Proteins ,Humans ,Luminescent Proteins ,Mice ,Mice ,Transgenic ,Pancreatic Neoplasms ,Stromal Cells ,Transforming Growth Factor beta ,Tumor Microenvironment ,BxPC-3 ,cancer cells ,color-coded intravital imaging ,GFP ,orthotopic mouse model ,pancreatic cancer ,RFP ,stromal cells ,TGF- inhibitor ,TGF-β inhibitor ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-β (TGF-β) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor.
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- 2017
34. Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice.
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Zhang, Yong, Cao, Wenluo, Toneri, Makoto, Zhang, Nan, Kiyuna, Tasuku, Murakami, Takashi, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Li, Shukuan, Wang, Xiaoen, Ma, Huaiyu, Singh, Arun S, Eilber, Fritz C, Hoffman, Robert M, and Zhao, Ming
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Salmonella typhimurium A1-R ,VNP20009 ,biodistribution ,efficacy ,toxicity ,tumor targeting ,Digestive Diseases ,Cancer ,Oncology and Carcinogenesis - Abstract
Salmonella typhimurium A1-R (S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 × 105 and 5 × 105 were tolerated. A single dose of 1 × 106 resulted in mouse death. S. typhimurium A1-R (5 × 105 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of S. typhimurium A1-R.
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- 2017
35. Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
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Murakami, Takashi, Li, Shukuan, Han, Qinghong, Tan, Yuying, Kiyuna, Tasuku, Igarashi, Kentaro, Kawaguchi, Kei, Hwang, Ho Kyoung, Miyake, Kentaro, Singh, Arun S, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Hiroshima, Yukihiko, Lwin, Thinzar M, DeLong, Jonathan C, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Mice ,Nude ,Disease Models ,Animal ,Carbon-Sulfur Lyases ,Recombinant Proteins ,Antimetabolites ,Antineoplastic ,Biopsy ,Tumor Burden ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Male ,Sarcoma ,Ewing ,Ewing’s sarcoma ,methionine dependence ,nude mice ,patient-derived orthotopic xenograft ,recalcitrant cancer ,recombinant methioninase ,Ewing's sarcoma ,Brain Disorders ,Pediatric Cancer ,Biotechnology ,Pediatric ,Cancer ,Rare Diseases ,Pediatric Research Initiative ,Oncology and Carcinogenesis - Abstract
Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.
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- 2017
36. High-efficacy targeting of colon-cancer liver metastasis with Salmonella typhimurium A1-R via intra-portal-vein injection in orthotopic nude-mouse models
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Kawaguchi, Kei, Murakami, Takashi, Suetsugu, Atsushi, Kiyuna, Tasuku, Igarashi, Kentaro, Hiroshima, Yukihiko, Zhao, Ming, Zhang, Yong, Bouvet, Michael, Clary, Bryan M, Unno, Michiaki, and Hoffman, Robert M
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Digestive Diseases ,Emerging Infectious Diseases ,Colo-Rectal Cancer ,Cancer ,Rare Diseases ,Liver Disease ,Prevention ,Animals ,Antineoplastic Agents ,Colonic Neoplasms ,HT29 Cells ,Humans ,Injections ,Intravenous ,Liver Neoplasms ,Mice ,Mice ,Nude ,Portal Vein ,Salmonella Infections ,Animal ,Salmonella typhimurium ,Xenograft Model Antitumor Assays ,Salmonella typhimurium A1-R ,tumor targeting ,intra-portal vein injection ,liver metastasis ,colon cancer ,nude mice ,orthotopic ,Oncology and Carcinogenesis - Abstract
Liver metastasis is the main cause of colon cancer-related death and is a recalcitrant disease. We report here the efficacy and safety of intra-portal-vein (iPV) targeting of Salmonella typhimurium A1-R on colon cancer liver metastasis in a nude-mouse orthotopic model. Nude mice with HT29 human colon cancer cells, expressing red fluorescent protein (RFP) (HT29-RFP), growing in the liver were administered S. typhimurium A1-R by either iPV (1×104 colony forming units (CFU)/100 μl) or, for comparison, intra-venous injection (iv; 5×107 CFU/100 μl). Similar amounts of bacteria were delivered to the liver with the two doses, indicating that iPV delivery is 5×103 times more efficient than iv delivery. Treatment efficacy was evaluated by tumor fluorescent area (mm2) and total fluorescence intensity. Tumor fluorescent area and fluorescence intensity highly correlated (p
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- 2017
37. Labeling the Stroma of a Patient-Derived Orthotopic Xenograft (PDOX) Mouse Model of Undifferentiated Pleomorphic Soft-Tissue Sarcoma With Red Fluorescent Protein for Rapid Non-Invasive Imaging for Drug Screening.
- Author
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Kiyuna, Tasuku, Murakami, Takashi, Tome, Yasunori, Igarashi, Kentaro, Kawaguchi, Kei, Russell, Tara, Eckardt, Mark A, Crompton, Joseph, Singh, Arun, Bernthal, Nicholas, Bukata, Susan, Federman, Noah, Kanaya, Fuminori, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Mice ,Transgenic ,Humans ,Mice ,Mice ,Nude ,Sarcoma ,Neoplasms ,Experimental ,Luminescent Proteins ,Xenograft Model Antitumor Assays ,Cell Tracking ,CONFOCAL ,IMAGING ,NONINVASIVE ,PDOX ,PLEOMORPHIC ,RED FLUORESCENT PROTEIN ,SARCOMA ,SOFT TISSUE ,STROMA ,TRANSGENIC NUDE MOUSE ,UNDIFFERENTIATED ,Transgenic ,Nude ,Neoplasms ,Experimental ,Biochemistry & Molecular Biology ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Our laboratory pioneered patient-derived orthotopic xenograft (PDOX) mouse models using surgical orthotopic implantation (SOI). PDOX models are patient-like, in contrast to the ectopic subcutaneous-transplant cancer models. In the present study, we demonstrate that an undifferentiated pleomorphic soft-tissue sarcoma (UPS-STS) PDOX model acquired bright RFP-expressing stroma through one passage in red fluorescent protein (RFP) transgenic mice, which upon passage to non-colored nude mice was non-invasively imageable. A PDOX nude mouse model of UPS-STS was established in the biceps femoris of nude mice. After the tumors grew to a diameter of 10 mm, the tumors were subsequently passaged to RFP transgenic mice, and after tumor growth were then passaged to non-transgenic nude mice. Tumors were divided into small fragments and transplanted in the biceps femoris at each passage. The OV100 Small Animal Fluorescence Imaging System and FV1000 laser scanning confocal microscope were used to image RFP fluorescence in the UPS-STS PDOX models. UPS-STS PDOX tumors, previously grown in RFP transgenic nude mice for only one passage, had very bright fluorescence and after passage to non-transgenic nude mice maintained the bright fluorescence and were non-invasively imageable. FV1000 confocal imaging revealed diffusely distributed bright RFP stromal cells in the PDOX tumor, both in RFP transgenic mice and after passage to non-transgenic mice. These results demonstrate a powerful method to make the PDOX UPS-STS model brightly fluorescent for non-invasive imaging, as well as for confocal microscopy of individual stromal cells associated with the tumor. The RFP-labeled UPS PDOX has the potential to rapidly screen for novel effective agents for individual patients, including stroma-targeting drugs, whereby the stromal cells are a visual target. J. Cell. Biochem. 118: 361-365, 2017. © 2016 Wiley Periodicals, Inc.
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- 2017
38. Patient-derived orthotopic xenograft (PDOX) mouse model of adult rhabdomyosarcoma invades and recurs after resection in contrast to the subcutaneous ectopic model
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Igarashi, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Murakami, Takashi, Miwa, Shinji, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Singh, Arun, Kimura, Hiroaki, Hayashi, Katsuhiro, Yamamoto, Norio, Tsuchiya, Hiroyuki, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Rare Diseases ,Pediatric ,Cancer ,Adult ,Aged ,Animals ,Cell Proliferation ,Disease-Free Survival ,Humans ,Male ,Mice ,Nude ,Neoplasm Invasiveness ,Neoplasm Recurrence ,Local ,Rhabdomyosarcoma ,Subcutaneous Tissue ,Time Factors ,Xenograft Model Antitumor Assays ,muscle ,nude mouse ,patient-derived orthotopic xenograft ,PDOX ,rhabdomyosarcoma ,resection ,recurrence ,subcutaneous ,tumor growth rate ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Rhabdomyosarcoma (RMS) is a rare mesenchymal tumor. The aim of the present study was to develop a patient-derived orthotopic xenograft (PDOX) mouse model of RMS and compare the PDOX model to a subcutaneous (s.c.)-transplant model. A patient RMS from a striated muscle was grown orthotopically in the right biceps femoris muscle and right quadriceps muscle of nude mice to establish a PDOX model, as well as under the skin to establish an s.c.ModelPDOX tumors grew at a statistically-significant faster rate compared to the s.c. tumors. Recurrence after surgical resection occurred only in PDOX tumors, not in the s.c.ModelHistologically, only the PDOX model was shown to be invasive. In conclusion, these results indicate that the PDOX model of adult RMS is malignant and the subcutaneous model is benign. These results emphasize that a proper tumor microenvironment is necessary for patient-like behavior of a tumor in a mouse model.
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- 2017
39. Clinical Factors That Affect the Establishment of Soft Tissue Sarcoma Patient-Derived Orthotopic Xenografts: A University of California, Los Angeles, Sarcoma Program Prospective Clinical Trial.
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Russell, Tara, Eckardt, Mark, Murakami, Takashi, Elliott, Irmina, Kawaguchi, Kei, Kiyuna, Tasuku, Igarashi, Kentaro, Li, Yungfeng, Crompton, Joseph, Graham, Danielle, Dry, Sarah, Yanagawa, Jane, Chmielowski, Bartosz, Singh, Arun, Eilber, Frederick, Bernthal, Nicholas, Hoffman, Robert, Kalbasi, Anusha, and Federman, Noah
- Abstract
PURPOSE: Given the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment. PATIENTS AND METHODS: From May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis. RESULTS: Only high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER(31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant (P = .180). CONCLUSION: To our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment.
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- 2017
40. Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel.
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Murakami, Takashi, Murata, Takuya, Kawaguchi, Kei, Kiyuna, Tasuku, Igarashi, Kentaro, Hwang, Ho Kyoung, Hiroshima, Yukihiko, Hozumi, Chihiro, Komatsu, Shin, Kikuchi, Takashi, Lwin, Thinzar M, Delong, Jonathan C, Miyake, Kentaro, Zhang, Yong, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
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Cancer ,Albumins ,Animals ,Antinematodal Agents ,Cisplatin ,Dose-Response Relationship ,Drug ,Drug Resistance ,Neoplasm ,Female ,Humans ,Mice ,Nude ,Paclitaxel ,Time Factors ,Tumor Burden ,Uterine Cervical Neoplasms ,Xenograft Model Antitumor Assays ,Cervical cancer ,patient-derived othotopic xenograft ,PDOX ,nude mice ,drug response ,cispatinum ,nab-paclitaxel ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundCervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective.Materials and methodsCervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX.ResultsH&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p
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- 2017
41. Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug.
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Murakami, Takashi, Igarashi, Kentaro, Kawaguchi, Kei, Kiyuna, Tasuku, Zhang, Yong, Zhao, Ming, Hiroshima, Yukihiko, Nelson, Scott D, Dry, Sarah M, Li, Yunfeng, Yanagawa, Jane, Russell, Tara, Federman, Noah, Singh, Arun, Elliott, Irmina, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Nude ,Salmonella typhimurium ,Osteosarcoma ,Bone Neoplasms ,Necrosis ,Phenylurea Compounds ,Niacinamide ,Antineoplastic Agents ,Protein Kinase Inhibitors ,Biological Therapy ,Tumor Burden ,Xenograft Model Antitumor Assays ,Drug Resistance ,Neoplasm ,Time Factors ,Adolescent ,Male ,Molecular Targeted Therapy ,Sorafenib ,Salmonella typhimurium A1-R ,nude mouse ,osteosarcoma ,patient-derived xenograft ,tumor-targeting ,Mice ,Nude ,Drug Resistance ,Neoplasm ,Oncology and Carcinogenesis - Abstract
Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p
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- 2017
42. Clinical Factors That Affect the Establishment of Soft Tissue Sarcoma Patient-Derived Orthotopic Xenografts: A University of California, Los Angeles, Sarcoma Program Prospective Clinical Trial.
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Russell, Tara A, Eckardt, Mark A, Murakami, Takashi, Elliott, Irmina A, Kawaguchi, Kei, Kiyuna, Tasuku, Igarashi, Kentaro, Li, Yungfeng, Crompton, Joseph G, Graham, Danielle S, Dry, Sarah M, Bernthal, Nicholas, Yanagawa, Jane, Kalbasi, Anusha, Federman, Noah, Chmielowski, Bartosz, Singh, Arun S, Hoffman, Robert M, and Eilber, Fritz C
- Abstract
PurposeGiven the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment.Patients and methodsFrom May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis.ResultsOnly high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER(31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant (P = .180).ConclusionTo our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment.
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- 2017
43. Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model
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Kawaguchi, Kei, Igarashi, Kentaro, Murakami, Takashi, Chmielowski, Bartosz, Kiyuna, Tasuku, Zhao, Ming, Zhang, Yong, Singh, Arun, Unno, Michiaki, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Eilber, Fritz C, and Hoffman, Robert M
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Brain Disorders ,Cancer ,Aged ,Animals ,Antineoplastic Agents ,Alkylating ,Dacarbazine ,Female ,Humans ,Melanoma ,Mice ,Mice ,Nude ,Mutation ,Proto-Oncogene Proteins B-raf ,Salmonella typhimurium ,Temozolomide ,Xenograft Model Antitumor Assays ,melanoma ,PDOX ,nude mice ,orthotopic ,drug-response ,Oncology and Carcinogenesis - Abstract
Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients.
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- 2016
44. Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model
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Kawaguchi, Kei, Murakami, Takashi, Chmielowski, Bartosz, Igarashi, Kentaro, Kiyuna, Tasuku, Unno, Michiaki, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Eilber, Fritz C, and Hoffman, Robert M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Biotechnology ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Aged ,Animals ,Antineoplastic Agents ,Azetidines ,Drug Resistance ,Neoplasm ,Female ,Humans ,Indoles ,Melanoma ,Mice ,Mitogen-Activated Protein Kinase Kinases ,Mutation ,Piperidines ,Proto-Oncogene Proteins B-raf ,Pyridones ,Pyrimidinones ,Sulfonamides ,Vemurafenib ,Xenograft Model Antitumor Assays ,melanoma ,PDOX ,nude mice ,orthotopic ,drug-response ,Oncology and carcinogenesis - Abstract
Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0.3 mg/kg); and G5, cobimetinib (COB) (5 mg/kg). Each drug was administered orally, daily for 14 consecutive days. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, TRA, an MEK inhibitor, was the only agent of the 4 tested that caused tumor regression (P < 0.001 at day 14). In contrast, another MEK inhibitor, COB, could slow but not arrest growth or cause regression of the melanoma. First-line therapy TEM could slow but not arrest tumor growth or cause regression. The patient in this study had a BRAF-V600E-mutant melanoma and would be considered to be a strong candidate for VEM as first-line therapy, since VEM targets this mutation. However, VEM was not effective. The PDOX model thus helped identify the very-high efficacy of TRA against the melanoma PDOX and is a promising drug for this patient. These results demonstrate the powerful precision of the PDOX model for cancer therapy, not achievable by genomic analysis alone.
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- 2016
45. Disintegrin targeting of an α v β 3 integrin-over-expressing high-metastatic human osteosarcoma with Echistatin inhibits cell proliferation, migration, invasion and adhesion in vitro
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Tome, Yasunori, Kimura, Hiroaki, Kiyuna, Tasuku, Sugimoto, Naotoshi, Tsuchiya, Hiroyuki, Kanaya, Fuminori, Bouvet, Michael, and Hoffman, Robert M
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Pediatric ,Clinical Research ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Cancer ,Antineoplastic Agents ,Bone Neoplasms ,Cell Adhesion ,Cell Line ,Tumor ,Cell Movement ,Cell Proliferation ,Disintegrins ,Humans ,Integrin alphaVbeta3 ,Intercellular Signaling Peptides and Proteins ,Neoplasm Invasiveness ,Osteosarcoma ,Peptides ,alpha(v)beta(3) integrin ,echistatin ,green fluorescent protein/red fluorescent protein ,osteosarcoma ,metastasis ,αv β3 integrin ,Oncology and Carcinogenesis - Abstract
The in vitro efficacy of the disintegrin echistatin was tested on a high-metastatic variant of 143B human osteosarcoma, 143B-LM4, which over-expresses αvβ3 integrin. Echistatin is an RGD cyclic peptide and an antagonist of αvβ3 integrin. In the present study, echistatin inhibited cell proliferation, migration, invasion, and adhesion of 143B-LM4 cells. 143B-LM4 cell proliferation decreased after treatment with echistatin in a time-dependent and dose-dependent manner (P
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- 2016
46. Disintegrin targeting of an αvβ3 integrin-over-expressing high-metastatic human osteosarcoma with echistatin inhibits cell proliferation, migration, invasion and adhesion in vitro.
- Author
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Tome, Yasunori, Kimura, Hiroaki, Kiyuna, Tasuku, Sugimoto, Naotoshi, Tsuchiya, Hiroyuki, Kanaya, Fuminori, Bouvet, Michael, and Hoffman, Robert M
- Subjects
Cell Line ,Tumor ,Humans ,Osteosarcoma ,Bone Neoplasms ,Neoplasm Invasiveness ,Peptides ,Disintegrins ,Integrin alphaVbeta3 ,Antineoplastic Agents ,Cell Adhesion ,Cell Proliferation ,Cell Movement ,echistatin ,green fluorescent protein/red fluorescent protein ,metastasis ,osteosarcoma ,αv β3 integrin ,Intercellular Signaling Peptides and Proteins ,alpha(v)beta(3) integrin ,Cell Line ,Tumor ,Oncology and Carcinogenesis - Abstract
The in vitro efficacy of the disintegrin echistatin was tested on a high-metastatic variant of 143B human osteosarcoma, 143B-LM4, which over-expresses αvβ3 integrin. Echistatin is an RGD cyclic peptide and an antagonist of αvβ3 integrin. In the present study, echistatin inhibited cell proliferation, migration, invasion, and adhesion of 143B-LM4 cells. 143B-LM4 cell proliferation decreased after treatment with echistatin in a time-dependent and dose-dependent manner (P
- Published
- 2016
47. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.
- Author
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Murakami, Takashi, Singh, Arun S, Kiyuna, Tasuku, Dry, Sarah M, Li, Yunfeng, James, Aaron W, Igarashi, Kentaro, Kawaguchi, Kei, DeLong, Jonathan C, Zhang, Yong, Hiroshima, Yukihiko, Russell, Tara, Eckardt, Mark A, Yanagawa, Jane, Federman, Noah, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Bone Neoplasms ,Imidazoles ,Piperazines ,Pyrazines ,Pyridines ,Doxorubicin ,Receptor ,IGF Type 1 ,RNA-Binding Protein FUS ,Oncogene Proteins ,Fusion ,Xenograft Model Antitumor Assays ,Drug Resistance ,Neoplasm ,Female ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase Inhibitor p18 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Molecular Targeted Therapy ,Sarcoma ,Ewing ,Ewing’s sarcoma ,PDOX ,linsitinib ,palbociclib ,patient-derived orthotopic xenograft ,Ewing's sarcoma ,Pediatric ,Pediatric Research Initiative ,Orphan Drug ,Cancer ,Rare Diseases ,Pediatric Cancer ,Oncology and Carcinogenesis - Abstract
Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.
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- 2016
48. High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model.
- Author
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Kiyuna, Tasuku, Murakami, Takashi, Tome, Yasunori, Kawaguchi, Kei, Igarashi, Kentaro, Zhang, Yong, Zhao, Ming, Li, Yunfeng, Bouvet, Michael, Kanaya, Fuminori, Singh, Arun, Dry, Sarah, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Salmonella Infections ,Imidazoles ,Quinolines ,Doxorubicin ,Antibiotics ,Antineoplastic ,Xenograft Model Antitumor Assays ,Drug Resistance ,Neoplasm ,Female ,Dendritic Cell Sarcoma ,Follicular ,GFP ,Salmonella typhimurium A1-R ,sarcoma ,soft-tissue ,tumor-targeting ,PDOX ,nude mice ,doxorubicin ,Orphan Drug ,Biotechnology ,Emerging Infectious Diseases ,Rare Diseases ,Cancer ,Oncology and Carcinogenesis - Abstract
Follicular dendritic-cell sarcoma (FDCS) is a rare and recalcitrant disease. In the present study, a patient-derived orthotopic xenograft (PDOX) mouse model of FDCS was established in the biceps muscle of nude mice. The FDCS PDOX was resistant to both doxorubicin (DOX) and NVP-BEZ235, dactolisib (BEZ) an experimental agent which is a dual pan-phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor. However, in contrast to DOX and BEZ, the FDCS PDOX was sensitive to the tumor-targeting bacterial strain, Salmonella typhimurium A1-R (S. typhimurium A1-R). The combination of S. typhimurium A1-R and either DOX or BEZ did not increase the antitumor efficacy of S. typhimurium A1-R, indicating that DOX and BEZ were not active in this PDOX model. The efficacy of S. typhimurium A1-R in this recalcitrant FDCS gives strong impetus to move bacterial therapy to clinical trials for this disease. The findings of the present study are of particular importance since it demonstrates that S. typhimurium A1-R is effective in a PDOX model of FDCS established from a patient who failed DOX therapy.
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- 2016
49. Fluorescence Imaging of Tumors in Human Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models
- Author
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Hoffman, Robert M., Suetsugu, Atsushi, Kiyuna, Tasuku, Yano, Shuya, Bouvet, Michael, Coleman, William B., Series editor, Tsongalis, Gregory J., Series editor, and Hoffman, Robert M., editor
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- 2017
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50. Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma
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Igarashi, Kentaro, Kawaguchi, Kei, Li, Shukuan, Han, Qinghong, Tan, Yuying, Murakami, Takashi, Kiyuna, Tasuku, Miyake, Kentaro, Miyake, Masuyo, Singh, Arun S., Eckardt, Mark A., Nelson, Scott D., Russell, Tara A., Dry, Sarah M., Li, Yunfeng, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Tsuchiya, Hiroyuki, Singh, Shree Ram, Eilber, Fritz C., and Hoffman, Robert M.
- Published
- 2018
- Full Text
- View/download PDF
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