633 results on '"Hiroshima, Yukihiko"'
Search Results
2. Differential diagnosis of uterine adenosarcoma: identification of JAZF1-BCORL1 rearrangement by comprehensive cancer genomic profiling
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Hasegawa, Chie, Washimi, Kota, Hiroshima, Yukihiko, Kasajima, Rika, Kikuchi, Keiji, Notomi, Tsuguto, Kato, Hisamori, Hiruma, Toru, Sato, Shinya, Okubo, Yoichiro, Yoshioka, Emi, Ono, Kyoko, Miyagi, Yohei, and Yokose, Tomoyuki
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- 2023
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3. Genomic landscape and clinical features of advanced thyroid carcinoma: a national database study in Japan
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Toda, Soji, primary, Hiroshima, Yukihiko, additional, Iwasaki, Hiroyuki, additional, and Masudo, Katsuhiko, additional
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- 2024
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4. Evaluation of pancreatic cancer specimens for comprehensive genomic profiling
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Washimi, Kota, primary, Hiroshima, Yukihiko, additional, Sato, Shinya, additional, Ueno, Makoto, additional, Kobayashi, Satoshi, additional, Yamamoto, Naoto, additional, Hasegawa, Chie, additional, Yoshioka, Emi, additional, Ono, Kyoko, additional, Okubo, Yoichiro, additional, Yokose, Tomoyuki, additional, and Miyagi, Yohei, additional
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- 2024
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5. Clinical Significance of Tryptophanyl-tRNA Synthetase 1 Gene Expression in Patients With Locally Advanced Gastric Cancer
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OSHIMA, TAKASHI, primary, HASHIMOTO, ITARU, additional, HIROSHIMA, YUKIHIKO, additional, KIMURA, YAYOI, additional, TANABE, MIE, additional, ONUMA, SHIZUNE, additional, MORITA, JUNYA, additional, NAGASAWA, SHINSUKE, additional, KANEMATSU, KYOHEI, additional, AOYAMA, TORU, additional, YAMADA, TAKANOBU, additional, OGATA, TAKASHI, additional, RINO, YASUSHI, additional, SAITO, AYA, additional, and MIYAGI, YOHEI, additional
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- 2024
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6. 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
7. RT-PCR of peritoneal washings predicts peritoneal pancreatic cancer recurrence
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Sato, Kei, Mori, Ryutaro, Hiroshima, Yukihiko, Oba, Mari S, Matsuyama, Ryusei, Bouvet, Michael, Hoffman, Robert M, and Endo, Itaru
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Biotechnology ,Prevention ,Digestive Diseases ,Cancer ,Rare Diseases ,Pancreatic Cancer ,Adult ,Aged ,Aged ,80 and over ,Biomarkers ,Tumor ,Chemotherapy ,Adjuvant ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Male ,Middle Aged ,Mucin-1 ,Neoplasm Recurrence ,Local ,Pancreatectomy ,Pancreatic Neoplasms ,Peritoneal Lavage ,Peritoneal Neoplasms ,Prognosis ,Prospective Studies ,RNA ,Messenger ,Reverse Transcriptase Polymerase Chain Reaction ,Survival Rate ,Pancreatic cancer ,Peritoneal washing ,Predictive risk factor ,Recurrence ,Reverse transcriptase ,PCR ,Clinical Sciences ,Surgery ,Clinical sciences - Abstract
BACKGROUND:Peritoneal recurrence of pancreatic cancer is a frequent and lethal outcome after R0 resection. A method to predict peritoneal recurrence could be helpful in its prevention. MATERIALS AND METHODS:Peritoneal washings were prospectively obtained from 29 patients in whom R0 resection was performed. Cytological examination (CY) and real-time reverse transcription polymerase chain reaction (RT-PCR) of the peritoneal washing for the detection of cancer-related genes, CEACAM5, KRT7, KRAS, and MUC1, were performed. Clinicopathological characteristics and real-time RT-PCR results of the peritoneal washing were compared between patients whose pancreatic cancer recurred peritoneally (n = 7) and those patients who it did not recur (n = 22). RESULTS:Only one CY-positive (CY+) case was detected, and that patient recurred. MUC1 mRNA expression was significantly higher in the recurrence group (P = 0.015). Cumulative incidence-function analysis demonstrated that peritoneal recurrence rate was significantly higher in MUC1-positive (MUC1+) patients (P = 0.044). MUC1+ patients had significantly decreased disease-free survival (P = 0.009) and disease-specific survival (P = 0.031). MUC1 protein was detected in the primary tumor in 18 of 29 patients. However, no significant difference was observed in the expression of MUC1 protein in peritoneal washings from the primary tumor (P = 0.579). CONCLUSIONS:High expression of MUC1 mRNA in peritoneal washings is a significant risk factor for peritoneal recurrence of pancreatic cancer after R0 resection along with poor disease-specific survival. RT-PCR of MUC1 mRNA in peritoneal washing may be useful for individualization of adjuvant chemotherapy.
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- 2018
8. 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.
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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
9. 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
10. 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.
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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
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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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. Effective fluorescence‐guided surgery of liver metastasis using a fluorescent anti‐CEA antibody
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Hiroshima, Yukihiko, Lwin, Thinzar M, Murakami, Takashi, Mawy, Ali A, Kuniya, Tanaka, Chishima, Takashi, Endo, Itaru, Clary, Bryan M, Hoffman, Robert M, and Bouvet, Michael
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Colo-Rectal Cancer ,Digestive Diseases ,Animals ,Antibodies ,Monoclonal ,Carcinoembryonic Antigen ,Colorectal Neoplasms ,Fluorescent Antibody Technique ,Direct ,Fluorescent Dyes ,HT29 Cells ,Hepatectomy ,Humans ,Liver Neoplasms ,Mice ,Mice ,Nude ,Neoplasm Transplantation ,Optical Imaging ,Random Allocation ,Treatment Outcome ,fluorescence-guided surgery ,colon-cancer liver metastasis ,orthotopic-liver metastasis model ,fluorescent anti-CEA antibody ,survival ,disease-free survival ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Background and objectivesDelineation of adequate tumor margins is critical in oncologic surgery, particularly in resection of metastatic lesions. Surgeons are limited in visualization with bright-light surgery, but fluorescence-guided surgery (FGS) has been efficacious in helping the surgeon achieve negative margins.MethodsThe present study uses FGS in a mouse model that has undergone surgical orthotopic implantation (SOI) of colorectal liver metastasis tagged with green fluorescent protein (GFP). An anti-CEA antibody conjugated to DyLight 650 was used to highlight the tumor.ResultsThe fluorescent antibody clearly demarcated the lesion at deeper tissue depth compared to GFP. Fluorescence of the anti-CEA-DyLight650 showed maximal tumor-to-liver contrast at 72 hr. Fifteen mice underwent bright-light surgery (BLS) versus FGS with GFP versus FGS with anti-CEA-DyLight650. Mice that underwent FGS had a significantly smaller area of residual tumor (P
- Published
- 2016
18. Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy
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Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Zhang, Nan, Murakami, Takashi, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
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Cancer ,Rare Diseases ,Good Health and Well Being ,Animals ,Benzamides ,Disease Models ,Animal ,Female ,Humans ,Mice ,Neoplasm Metastasis ,Precision Medicine ,Pyridines ,Uterine Cervical Neoplasms ,Xenograft Model Antitumor Assays ,Patient-derived orthotopic xenograft ,PDOX ,cervical cancer ,nude mouse ,primary tumor ,patient-derived orthotopic xenograft ,Oncology and Carcinogenesis - Abstract
Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy.
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- 2016
19. 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.
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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
20. Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) model
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Murakami, Takashi, DeLong, Jonathan, Eilber, Fritz C, Zhao, Ming, Zhang, Yong, Zhang, Nan, Singh, Arun, Russell, Tara, Deng, Samantha, Reynoso, Jose, Quan, Cuong, Hiroshima, Yukihiko, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Chawla, Sant, Endo, Itaru, and Hoffman, Robert M
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Rare Diseases ,Pediatric Cancer ,Orphan Drug ,Pediatric ,Cancer ,Emerging Infectious Diseases ,Biotechnology ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Doxorubicin ,Humans ,Mice ,Mice ,Nude ,Salmonella Infections ,Salmonella typhimurium ,Sarcoma ,Xenograft Model Antitumor Assays ,nude mice ,patient-derived orthotopic xenograft ,soft tissue sarcoma ,Salmonella typhimurium A1-R ,tumor-targeting ,Oncology and Carcinogenesis - Abstract
A patient with high grade undifferentiated pleomorphic soft-tissue sarcoma from a striated muscle was grown orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. Twenty PDOX mice were divided into 4 groups: G1, control without treatment; G2, Salmonella typhimurium (S. typhimurium)A1-R administered by intratumoral (i.t.) injection once a week for 4 weeks; G3, doxorubicin (DOX) administered by intraperitoneal (i.p.) injection once a week for 4 weeks; G4, S. typhimurium A1-R (i.t.) administered once a week for 2 weeks followed by i.p. doxorubicin once a week for 2 weeks. On day 25 from the initiation of treatment, tumor volume in G2, G3, and G4 was significantly lower than G1. Mice found without gross tumor included one mouse (20%) in G2; one mouse (20%) in G3; and 3 mice (60%) in G4. Body weight loss did not significantly differ between the 3 treated groups or from the untreated control. Histological examination revealed eradication of tumor only in G4 where mice were treated with S. typhimurium A1-R followed by DOX. Our present study indicates future clinical potential of combining S. typhimurium A1-R with chemotherapy such as DOX for soft tissue sarcoma patients.
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- 2016
21. Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model.
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Yano, Shuya, Takehara, Kiyoto, Miwa, Shinji, Kishimoto, Hiroyuki, Hiroshima, Yukihiko, Murakami, Takashi, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Nude ,Adenoviridae ,Colonic Neoplasms ,Liver Neoplasms ,Neoplasm Metastasis ,Telomerase ,Green Fluorescent Proteins ,Cell Line ,Tumor ,Mice ,Nude ,General Science & Technology - Abstract
Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.
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- 2016
22. Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model.
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Yamamoto, Mako, Zhao, Ming, Hiroshima, Yukihiko, Zhang, Yong, Shurell, Elizabeth, Eilber, Fritz C, Bouvet, Michael, Noda, Makoto, and Hoffman, Robert M
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Animals ,Humans ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Salmonella Infections ,Melanoma ,Disease Models ,Animal ,Antineoplastic Agents ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,Digestive Diseases ,Vaccine Related ,Emerging Infectious Diseases ,Cancer ,Foodborne Illness ,General Science & Technology - Abstract
Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer.
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- 2016
23. Adjuvant treatment with tumor-targeting Salmonella typhimurium A1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model
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Murakami, Takashi, Hiroshima, Yukihiko, Zhao, Ming, Zhang, Yong, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
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Rare Diseases ,Cancer ,Colo-Rectal Cancer ,Digestive Diseases ,Liver Disease ,Animals ,Biological Therapy ,Colonic Neoplasms ,Combined Modality Therapy ,Green Fluorescent Proteins ,HT29 Cells ,Hepatectomy ,Humans ,Liver Neoplasms ,Luminescent Proteins ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Salmonella typhimurium ,Time Factors ,Transfection ,Xenograft Model Antitumor Assays ,liver metastasis ,colon cancer ,RFP ,nude mice ,orthotopic models ,Oncology and Carcinogenesis - Abstract
Colon cancer liver metastasis is often the lethal aspect of this disease. Well-isolated metastases are candidates for surgical resection, but recurrence is common. Better adjuvant treatment is therefore needed to reduce or prevent recurrence. In the present study, HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used to establish liver metastases in nude mice. Mice with a single liver metastasis were randomized into bright-light surgery (BLS) or the combination of BLS and adjuvant treatment with tumor-targeting S. typhimurium A1-R. Residual tumor fluorescence after BLS was clearly visualized at high magnification by fluorescence imaging. Adjuvant treatment with S. typhimurium A1-R was highly effective to increase survival and disease-free survival after BLS of liver metastasis. The results suggest the future clinical potential of adjuvant S. typhimurium A1-R treatment after liver metastasis resection.
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- 2015
24. Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model
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Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Guzman, Miguel Garcia, Heim, Roger, Makings, Lew, Luiken, George A, Kobayashi, Hisataka, Tanaka, Kuniya, Endo, Itaru, Hoffman, Robert M, and Bouvet, Michael
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Pancreatic Cancer ,Rare Diseases ,Cancer ,Digestive Diseases ,Animals ,Antibodies ,Monoclonal ,Carcinoembryonic Antigen ,Humans ,Immunoenzyme Techniques ,Immunotherapy ,Mice ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Neoplasm ,Residual ,Pancreatic Neoplasms ,Photochemotherapy ,Photosensitizing Agents ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPhotoimmunotherapy (PIT) uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, to induce tumor necrosis after irradiation with NIR light to kill cancer cells, such as those that remain after surgery. The purpose of the present study was to sterilize the surgical bed after pancreatic cancer resection with PIT in carcinoembryonic antigen (CEA)-expressing, patient-derived, orthotopic xenograft (PDOX) nude mouse models.MethodsAfter confirmation of tumor engraftment, mice were randomized to two groups: bright light surgery (BLS)-only and BLS + PIT. Each treatment arm consisted of seven tumor-bearing mice. BLS was performed under standard bright-field with an MVX10 long-working distance, high-magnification microscope on all mice. For BLS + PIT, anti-CEA antibody conjugated with IR700 (anti-CEA-IR700) (50 µg) was injected intravenously in all mice 24 h before surgery. After the surgery, the resection bed was then irradiated with a red-light-emitting diode at 690 ± 5 nm with a power density of 150 mW/cm(2).ResultsAnti-CEA-IR700 labelled and illuminated the pancreatic cancer PDOX. Minimal residual cancer of the PDOX was detected by fluorescence after BLS. The local recurrence rate was 85.7 % for BLS-only and 28.6 % for BLS + PIT-treated mice (p = 0.05). The average recurrent tumor weight was 1149.0 ± 794.6 mg for BLS-only and 210.8 ± 336.9 mg for BLS + PIT-treated mice (p = 0.015).ConclusionAnti-CEA-IR700 was able to label and illuminate a pancreatic cancer PDOX nude mouse model sufficiently for PIT. PIT reduced recurrence by eliminating remaining residual cancer cells after BLS.
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- 2015
25. Color‐Coded Imaging of Breast Cancer Metastatic Niche Formation in Nude Mice
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Suetsugu, Atsushi, Momiyama, Masashi, Hiroshima, Yukihiko, Shimizu, Masahito, Saji, Shigetoyo, Moriwaki, Hisataka, Bouvet, Michael, and Hoffman, Robert M
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Biochemistry and Cell Biology ,Biological Sciences ,Breast Cancer ,Lung ,Cancer ,Liver Disease ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Breast Neoplasms ,Female ,Green Fluorescent Proteins ,Humans ,Liver Neoplasms ,Luminescent Proteins ,Mice ,Mice ,Nude ,Molecular Imaging ,Neoplasm Metastasis ,Tumor Microenvironment ,BREAST CANCER ,METASTATIS ,NICHE ,CANCER-ASSOCIATED FIBROBLASTS ,LUNG ,LIVER ,GFP ,RFP ,COLOR-CODED IMAGING ,Medical Physiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
We report here a color-coded imaging model in which metastatic niches in the lung and liver of breast cancer can be identified. The transgenic green fluorescent protein (GFP)-expressing nude mouse was used as the host. The GFP nude mouse expresses GFP in all organs. However, GFP expression is dim in the liver parenchymal cells. Mouse mammary tumor cells (MMT 060562) (MMT), expressing red fluorescent protein (RFP), were injected in the tail vein of GFP nude mice to produce experimental lung metastasis and in the spleen of GFP nude mice to establish a liver metastasis model. Niche formation in the lung and liver metastasis was observed using very high resolution imaging systems. In the lung, GFP host-mouse cells accumulated around as few as a single MMT-RFP cell. In addition, GFP host cells were observed to form circle-shaped niches in the lung even without RFP cancer cells, which was possibly a niche in which future metastasis could be formed. In the liver, as with the lung, GFP host cells could form circle-shaped niches. Liver and lung metastases were removed surgically and cultured in vitro. MMT-RFP cells and GFP host cells resembling cancer-associated fibroblasts (CAFs) were observed interacting, suggesting that CAFs could serve as a metastatic niche.
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- 2015
26. Therapeutic efficacy of tumor-targeting Salmonella typhimurium A1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models
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Murakami, Takashi, Hiroshima, Yukihiko, Zhao, Ming, Zhang, Yong, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
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Rare Diseases ,Cancer ,Liver Disease ,Digestive Diseases ,Colo-Rectal Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Biological Therapy ,Cell Proliferation ,Colorectal Neoplasms ,Flow Cytometry ,Green Fluorescent Proteins ,Humans ,Liver Neoplasms ,Mice ,Mice ,Nude ,Salmonella Infections ,Animal ,Salmonella typhimurium ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,nude mice ,orthotopic ,liver metastasis ,red fluorescent protein ,Salmonella typhimurium A1-R ,Oncology and Carcinogenesis - Abstract
Liver metastasis is the most frequent cause of death from colon and other cancers. Generally, liver metastasis is recalcitrant to treatment. The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R on liver metastasis in orthotopic mouse models. HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used in the present study. S. typhimurium A1-R infected HT-29 cells in a time-dependent manner, inhibiting cancer-cell proliferation in vitro. S. typhimurium A1-R promoted tumor necrosis and inhibited tumor growth in a subcutaneous tumor mouse model of HT-29-RFP. In orthotopic mouse models, S. typhimurium A1-R targeted liver metastases and significantly reduced their growth. The results of this study demonstrate the future clinical potential of S. typhimurium A1-R targeting of liver metastasis.
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- 2015
27. The combination of gemcitabine and docetaxel arrests a doxorubicin-resistant dedifferentiated liposarcoma in a patient-derived orthotopic xenograft model
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Miyake, Kentaro, Higuchi, Takashi, Oshiro, Hiromichi, Zhang, Zhiying, Sugisawa, Norihiko, Park, Jun Ho, Razmjooei, Sahar, Katsuya, Yuki, Barangi, Maryam, Li, Yunfeng, Nelson, Scott D., Murakami, Takashi, Homma, Yuki, Hiroshima, Yukihiko, Matsuyama, Ryusei, Bouvet, Michael, Chawla, Sant P., Singh, Shree Ram, Endo, Itaru, and Hoffman, Robert M.
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- 2019
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28. High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1
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Maezawa, Yukio, Sakamaki, Kentaro, Oue, Naohide, Kimura, Yayoi, Hashimoto, Itaru, Hara, Kentaro, Kano, Kazuki, Aoyama, Toru, Hiroshima, Yukihiko, Yamada, Takanobu, Yamamoto, Naoto, Ogata, Takashi, Ito, Hiroyuki, Cho, Haruhiko, Shiozawa, Manabu, Yoshikawa, Takaki, Morinaga, Soichiro, Rino, Yasushi, Yasui, Wataru, Masuda, Munetaka, Miyagi, Yohei, and Oshima, Takashi
- Published
- 2020
- Full Text
- View/download PDF
29. Photoimmunotherapy lowers recurrence after pancreatic cancer surgery in orthotopic nude mouse models
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Maawy, Ali A, Hiroshima, Yukihiko, Zhang, Yong, Garcia-Guzman, Miguel, Luiken, George A, Kobayashi, Hisataka, Hoffman, Robert M, and Bouvet, Michael
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Rare Diseases ,Digestive Diseases ,Pancreatic Cancer ,Cancer ,Animals ,Antibodies ,Monoclonal ,Carcinoembryonic Antigen ,Cell Line ,Tumor ,Chemotherapy ,Adjuvant ,Humans ,Indoles ,Isoindoles ,Mice ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Neoplasm Transplantation ,Pancreatectomy ,Pancreatic Neoplasms ,Photochemotherapy ,Photosensitizing Agents ,Treatment Outcome ,Pancreatic cancer ,Orthotopic mouse models ,Photoimmunotherapy ,CEA ,Surgery ,Clinical Sciences - Abstract
BackgroundPhotoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence.Materials and methodsAthymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 μg) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm(2) for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager.ResultsBLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm(2), 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm(2), 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001).ConclusionsPIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy.
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- 2015
30. Experimental Curative Fluorescence-guided Surgery of Highly Invasive Glioblastoma Multiforme Selectively Labeled With a Killer-reporter Adenovirus
- Author
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Yano, Shuya, Miwa, Shinji, Kishimoto, Hiroyuki, Toneri, Makoto, Hiroshima, Yukihiko, Yamamoto, Mako, Bouvet, Michael, Urata, Yasuo, Tazawa, Hiroshi, Kagawa, Shunsuke, Fujiwara, Toshiyoshi, and Hoffman, Robert M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Brain Cancer ,Brain Disorders ,Cancer ,Neurosciences ,Adenoviridae ,Animals ,Cell Line ,Tumor ,Disease Models ,Animal ,Disease-Free Survival ,Fluorescence ,Glioblastoma ,Green Fluorescent Proteins ,Humans ,Mice ,Mice ,Nude ,Neoplasm Recurrence ,Local ,Optical Imaging ,Biological Sciences ,Technology ,Medical and Health Sciences ,Biotechnology ,Genetics ,Clinical sciences ,Medical biotechnology - Abstract
Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS.
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- 2015
31. Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma
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Yano, Shuya, Miwa, Shinji, Kishimoto, Hiroyuki, Uehara, Fuminari, Tazawa, Hiroshi, Toneri, Makoto, Hiroshima, Yukihiko, Yamamoto, Mako, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M
- Subjects
Cancer ,Rare Diseases ,Adenoviridae ,Animals ,Cell Line ,Tumor ,Cells ,Cultured ,Fluorescence ,Genetic Vectors ,Green Fluorescent Proteins ,Luminescent Agents ,Luminescent Proteins ,Mice ,Mice ,Nude ,Optical Imaging ,Sarcoma ,Experimental ,Soft Tissue Neoplasms ,Surgery ,Computer-Assisted ,soft tissue sarcoma ,nude mice ,fluorescence-guided surgery ,adenovirus ,OBP-401 ,Oncology and Carcinogenesis - Abstract
Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.
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- 2015
32. Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice
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Matsumoto, Yasunori, Miwa, Shinji, Zhang, Yong, Zhao, Ming, Yano, Shuya, Uehara, Fuminari, Yamamoto, Mako, Hiroshima, Yukihiko, Toneri, Makoto, Bouvet, Michael, Matsubara, Hisahiro, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Cancer ,Rare Diseases ,Digestive Diseases ,Prevention ,Emerging Infectious Diseases ,Ovarian Cancer ,Orphan Drug ,Animals ,Bacterial Load ,Biological Therapy ,Cell Line ,Tumor ,Female ,Humans ,Injections ,Intraperitoneal ,Injections ,Intravenous ,Mice ,Nude ,Ovarian Neoplasms ,Peritoneal Neoplasms ,Salmonella typhimurium ,Time Factors ,Virulence ,Xenograft Model Antitumor Assays ,ovarian cancer ,orthotopic ,mouse model ,bacterial therapy ,Salmonella typhimurium A1-R ,Oncology and Carcinogenesis - Abstract
UnlabelledPeritoneal disseminated cancer is highly treatment resistant. We here report the efficacy of intraperitoneal (i.p.) administration of tumor-targeting Salmonella typhimurium A1-R in a nude mouse model of disseminated human ovarian cancer. The mouse model was established by intraperitoneal injection of the human ovarian cancer cell line SKOV3-GFP. Seven days after implantation, mice were treated with S. typhimurium A1-R via intravenous (i.v.) or i.p. administration at the same dose, 5 × 10(7) CFU, once per week. Both i.v. and i.p. treatments effected prolonged survival compared with the untreated control group (P=0.025 and P
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- 2015
33. Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC)
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Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Murakami, Takashi, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Endo, Itaru, Hoffman, Robert M, and Bouvet, Michael
- Subjects
Cancer ,Pancreatic Cancer ,Rare Diseases ,Biotechnology ,Digestive Diseases ,Adenocarcinoma ,Animals ,Antimetabolites ,Antineoplastic ,Chemotherapy ,Adjuvant ,Deoxycytidine ,Drug Resistance ,Neoplasm ,Fluorescent Dyes ,Heterografts ,Humans ,Light ,Mice ,Mice ,Inbred NOD ,Mice ,Nude ,Neoadjuvant Therapy ,Neoplasm Recurrence ,Local ,Neoplasm Transplantation ,Optical Imaging ,Pancreatectomy ,Pancreatic Neoplasms ,Random Allocation ,Transplantation ,Heterologous ,Treatment Outcome ,Gemcitabine ,Fluorescence-guided surgery ,Pancreatic cancer ,Patient derived orthotopic xenograft ,Neoadjuvant chemotherapy ,CEA ,PDOX ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
BackgroundThe aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model.MethodsA PDOX model was established from a CEA-positive tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS + NAC; FGS only; and FGS + NAC. An anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with a pancreatic cancer PDOX 24 h before surgery.ResultsThe PDOX was clearly labeled with fluorophore-conjugated anti-CEA antibody. Only one out of 8 mice had local recurrence in the FGS only group and zero out of 8 mice had local recurrence in the FGS + NAC which was significantly lower than BLS only or BLS + NAC mice, where local disease recurred in 6 out of 8 mice in each treatment group (p = 0.041 and p = 0.007, respectively). NAC did not significantly reduce recurrence rates when combined with either FGS or BLS.ConclusionThese results indicate that FGS can significantly reduce local recurrence compared to BLS in pancreatic cancer resistant to NAC.
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- 2015
34. Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam® histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging
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Yano, Shuya, Miwa, Shinji, Mii, Sumiyuki, Hiroshima, Yukihiko, Uehara, Fuminaru, Kishimoto, Hiroyuki, Tazawa, Hiroshi, Zhao, Ming, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M
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Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Bioengineering ,Animals ,Cell Culture Techniques ,Cell Cycle ,Cell Death ,Cell Line ,Tumor ,Cisplatin ,Computer Systems ,Female ,Fluorescence ,Gelatin Sponge ,Absorbable ,Humans ,Mice ,Nude ,Molecular Imaging ,Neoplasms ,Paclitaxel ,Time Factors ,Ubiquitination ,cell cycle ,chemotherapy ,FUCCI ,Gelfoam ,GFP ,imaging ,RFP ,stomach cancer ,Three dimensional-histoculture culture ,Gelfoam® ,Developmental Biology ,Biochemistry and cell biology - Abstract
The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after cessation of chemotherapy. These results suggested why most drugs currently in clinical use, which target cancer cells in S/G2/M, are mostly ineffective on solid tumors. In the present report, we used FUCCI imaging and Gelfoam® collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of cancer cells in Gelfoam® and in vivo tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G0/G1. This is in contrast to 2D culture where most cancer cells cycle. Similarly, the cancer cells responded similarly to toxic chemotherapy in Gelfoam® culture as in vivo, and very differently than cancer cells in 2D culture which were much more chemosensitive. Gelfoam® culture of FUCCI-expressing cancer cells offers the opportunity to image the cell cycle of cancer cells continuously and to screen for novel effective therapies to target quiescent cells, which are the majority in a tumor and which would have a strong probability to be effective in vivo.
- Published
- 2015
35. Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging
- Author
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Miwa, Shinji, Yano, Shuya, Kimura, Hiroaki, Yamamoto, Mako, Toneri, Makoto, Matsumoto, Yasunori, Uehara, Fuminari, Hiroshima, Yukihiko, Murakami, Takashi, Hayashi, Katsuhiro, Yamamoto, Norio, Bouvet, Michael, Fujiwara, Toshiyoshi, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Antineoplastic Agents ,Apoptosis ,Cell Cycle ,Cell Lineage ,Cisplatin ,Doxorubicin ,HeLa Cells ,Humans ,Mitosis ,Neoplasms ,Optical Imaging ,Proportional Hazards Models ,Time-Lapse Imaging ,cancer ,cell cycle ,chemoresistance ,chemosensitivity ,cisplatinum ,doxorubicin ,FUCCI ,GFP ,RFP ,HeLa ,time-lapse imaging ,tumor heterogeneity ,Hela Cells ,Developmental Biology ,Biochemistry and cell biology - Abstract
Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5 μM) or cisplatinum (CDDP) (5 μM) for 3 h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72 h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G2/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G2/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G2/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells.
- Published
- 2015
36. Fluorescence-Guided Surgery of Liver Metastasis in Orthotopic Nude-Mouse Models.
- Author
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Murakami, Takashi, Hiroshima, Yukihiko, Zhang, Yong, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
- Subjects
HT29 Cells ,Animals ,Humans ,Mice ,Mice ,Nude ,Liver Neoplasms ,Neoplasm ,Residual ,Disease Models ,Animal ,Recurrence ,Green Fluorescent Proteins ,Surgery ,Computer-Assisted ,Feasibility Studies ,Optical Imaging ,Disease Models ,Animal ,Nude ,Neoplasm ,Residual ,Surgery ,Computer-Assisted ,General Science & Technology - Abstract
We report here the development of fluorescence-guided surgery of liver metastasis. HT29 human colon cancer cells expressing green fluorescent protein (GFP) were initially injected in the spleen of nude mice. Three weeks later, established liver metastases were harvested and implanted on the left lobe of the liver in other nude mice in order to make an orthotopic liver metastasis model. Fourteen mice with a single liver metastasis were randomized into bright-light surgery (BLS) or fluorescence-guided surgery (FGS) groups. Seven mice were treated with BLS, seven were treated with FGS. Three weeks after implantation, the left lobe of the liver with a single metastasis was exposed through a median abdominal incision. BLS was performed under white light. FGS was performed using a hand-held portable fluorescence imaging system (Dino-Lite). Post-surgical residual tumor fluorescence was visualized with the OV100 Small Animal Imaging System. Residual tumor fluorescence after BLS was clearly visualized at high magnification with the OV100. In contrast, residual tumor fluorescence after FGS was not detected even at high magnification with the OV100. These results demonstrate the feasibility of FGS for liver metastasis.
- Published
- 2015
37. Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice.
- Author
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Hiroshima, Yukihiko, Zhao, Ming, Zhang, Yong, Zhang, Nan, Maawy, Ali, Murakami, Takashi, Mii, Sumiyuki, Uehara, Fuminari, Yamamoto, Mako, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
- Subjects
Animals ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Salmonella Infections ,Sarcoma ,Soft Tissue Neoplasms ,Disease Models ,Animal ,Sulfonamides ,Pyrimidines ,Deoxycytidine ,Antineoplastic Agents ,Xenograft Model Antitumor Assays ,Disease Models ,Animal ,Nude ,General Science & Technology - Abstract
A patient-derived nude-mouse model of soft-tissue sarcoma has been established and treated in the following groups: (1) untreated controls; (2) gemcitabine (GEM) (80 mg/kg, ip, weekly, 3 weeks); (3) Pazopanib (100 mg/kg, orally, daily, 3 weeks) and (4) Salmonella typhimurium A1-R (5 × 10(7) CFU/body, ip, weekly, 3 weeks). The sarcoma was resistant to GEM (p = 0.879). Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference (p = 0.115). S. typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice (p = 0.001). S. typhimurium A1-R was the only effective treatment for the soft-tissue sarcoma nude mouse model among all treatments including a newly approved multiple tyrosine kinase inhibitor; Pazopanib. These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma.
- Published
- 2015
38. Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern.
- Author
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Hiroshima, Yukihiko, Zhang, Yong, Zhang, Nan, Maawy, Ali, Mii, Sumiyuki, Yamamoto, Mako, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Murakami, Takashi, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Murata, Takuya, Endo, Itaru, and Hoffman, Robert M
- Subjects
Animals ,Humans ,Mice ,Mice ,Nude ,Cell Transformation ,Neoplastic ,Neoplasm Metastasis ,Disease Models ,Animal ,Receptor ,erbB-2 ,Uterine Cervical Neoplasms ,Female ,Receptor ,ErbB-2 ,Cell Transformation ,Neoplastic ,Disease Models ,Animal ,Nude ,Receptor ,ErbB-2 ,General Science & Technology - Abstract
Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient's cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient's cervical tumors resulted in primary growth but not metastasis.
- Published
- 2015
39. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.
- Author
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Hiroshima, Yukihiko, Zhang, Yong, Zhao, Ming, Zhang, Nan, Murakami, Takashi, Maawy, Ali, Mii, Sumiyuki, Uehara, Fuminari, Yamamoto, Mako, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M
- Subjects
Animals ,Humans ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Disease Models ,Animal ,Receptor ,erbB-2 ,Transplantation ,Heterologous ,Immunohistochemistry ,Uterine Cervical Neoplasms ,Female ,Trastuzumab ,Receptor ,ErbB-2 ,Disease Models ,Animal ,Nude ,Receptor ,ErbB-2 ,Transplantation ,Heterologous ,General Science & Technology - Abstract
We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.
- Published
- 2015
40. MUC1 selectively targets human pancreatic cancer in orthotopic nude mouse models.
- Author
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Park, Jeong Youp, Hiroshima, Yukihiko, Lee, Jin Young, Maawy, Ali A, Hoffman, Robert M, and Bouvet, Michael
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mice ,Nude ,Pancreatic Neoplasms ,Antibodies ,Monoclonal ,Fluorescent Dyes ,Immunochemistry ,Biosensing Techniques ,Mucin-1 ,Optical Imaging ,Antibodies ,Monoclonal ,Cell Line ,Tumor ,Nude ,General Science & Technology - Abstract
The goal of this study was to determine whether MUC1 antibody conjugated with a fluorophore could be used to visualize pancreatic cancer. Anti-MUC1 (CT2) antibody was conjugated with 550 nm or 650 nm fluorophores. Nude mouse were used to make subcutaneous and orthotopic models of pancreatic cancer. Western blot and flow cytometric analysis confirmed the expression of MUC1 in human pancreatic cancer cell lines including BxPC-3 and Panc-1. Immunocytochemistry with fluorophore conjugated anti-MUC1 antibody demonstrated fluorescent areas on the membrane of Panc-1 cancer cells. After injecting the conjugated anti-MUC1 antibodies via the tail vein, subcutaneously transplanted Panc-1 and BxPC-3 tumors emitted strong fluorescent signals. In the subcutaneous tumor models, the fluorescent signal from the conjugated anti-MUC1 antibody was noted around the margin of the tumor and space between the cells. The conjugated anti-MUC1 antibody bound the tumor in orthotopically-transplanted Panc-1 and BxPC-3 models enabling the tumors to be imaged. This study showed that fluorophore conjugated anti-MUC1 antibodies could visualize pancreatic tumors in vitro and in vivo and may help to improve the diagnosis and treatment of pancreatic cancer.
- Published
- 2015
41. Near infra-red photoimmunotherapy with anti-CEA-IR700 results in extensive tumor lysis and a significant decrease in tumor burden in orthotopic mouse models of pancreatic cancer.
- Author
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Maawy, Ali A, Hiroshima, Yukihiko, Zhang, Yong, Heim, Roger, Makings, Lew, Garcia-Guzman, Miguel, Luiken, George A, Kobayashi, Hisataka, Hoffman, Robert M, and Bouvet, Michael
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mice ,Nude ,Pancreatic Neoplasms ,Carcinoembryonic Antigen ,Antibodies ,Monoclonal ,Radiation-Sensitizing Agents ,Immunotherapy ,Phototherapy ,Tumor Burden ,Xenograft Model Antitumor Assays ,Infrared Rays ,Antibodies ,Monoclonal ,Cell Line ,Tumor ,Nude ,General Science & Technology - Abstract
Photoimmunotherapy (PIT) of cancer utilizes tumor-specific monoclonal antibodies conjugated to a photosensitizer phthalocyanine dye IR700 which becomes cytotoxic upon irradiation with near infrared light. In this study, we aimed to evaluate the efficacy of PIT on human pancreatic cancer cells in vitro and in vivo in an orthotopic nude mouse model. The binding capacity of anti-CEA antibody to BxPC-3 human pancreatic cancer cells was determined by FACS analysis. An in vitro cytotoxicity assay was used to determine cell death following treatment with PIT. For in vivo determination of PIT efficacy, nude mice were orthotopically implanted with BxPC-3 pancreatic tumors expressing green fluorescent protein (GFP). After tumor engraftment, the mice were divided into two groups: (1) treatment with anti-CEA-IR700 + 690 nm laser and (2) treatment with 690 nm laser only. Anti-CEA-IR700 (100 μg) was administered to group (1) via tail vein injection 24 hours prior to therapy. Tumors were then surgically exposed and treated with phototherapy at an intensity of 150 mW/cm2 for 30 minutes. Whole body imaging was done subsequently for 5 weeks using an OV-100 small animal imaging system. Anti-CEA-IR700 antibody bound to the BxPC3 cells to a high degree as shown by FACS analysis. Anti-CEA-IR700 caused extensive cancer cell killing after light activation compared to control cells in cytotoxicity assays. In the orthotopic models of pancreatic cancer, the anti-CEA-IR700 group had significantly smaller tumors than the control after 5 weeks (p
- Published
- 2015
42. Fluorescence-guided surgery of retroperitoneal-implanted human fibrosarcoma in nude mice delays or eliminates tumor recurrence and increases survival compared to bright-light surgery.
- Author
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Uehara, Fuminari, Hiroshima, Yukihiko, Miwa, Shinji, Tome, Yasunori, Yano, Shuya, Yamamoto, Mako, Matsumoto, Yasunori, Maehara, Hiroki, Tanaka, Kazuhiro, Bouvet, Michael, Kanaya, Fuminori, and Hoffman, Robert M
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mice ,Nude ,Fibrosarcoma ,Retroperitoneal Neoplasms ,Neoplasm Recurrence ,Local ,Green Fluorescent Proteins ,Surgery ,Computer-Assisted ,Fluorescence ,Female ,Optical Imaging ,Cell Line ,Tumor ,Nude ,Neoplasm Recurrence ,Local ,Surgery ,Computer-Assisted ,General Science & Technology - Abstract
The aim of this study is to determine if fluorescence-guided surgery (FGS) can eradicate human fibrosarcoma growing in the retroperitoneum of nude mice. One week after retroperitoneal implantation of human HT1080 fibrosarcoma cells, expressing green fluorescent protein (GFP) (HT-1080-GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 22). After BLS, mice were randomized into 2 treatment groups; BLS-only (n = 11) or the combination of BLS + FGS (n = 11). The residual tumors remaining after BLS were resected with FGS using a hand-held portable imaging system under fluorescence navigation. The average residual tumor area after BLS + FGS was significantly smaller than after BLS-only (0.4 ± 0.4 mm(2) and 10.5 ± 2.4 mm(2), respectively; p = 0.006). Five weeks after surgery, the fluorescent-tumor areas of BLS- and BLS + FGS-treated mice were 379 ± 147 mm(2) and 11.7 ± 6.9 mm(2), respectively, indicating that FGS greatly inhibited tumor recurrence compared to BLS. The combination of BLS + FGS significantly decreased fibrosarcoma recurrence compared to BLS-only treated mice (p < 0.001). Mice treated with BLS+FGS had a significantly higher disease-free survival rate than mice treated with BLS-only at five weeks after surgery. These results suggest that combination of BLS + FGS significantly reduced the residual fibrosarcoma volume after BLS and improved disease-free survival.
- Published
- 2015
43. MiR-194-5p in Pancreatic Ductal Adenocarcinoma Peritoneal Washings is Associated with Peritoneal Recurrence and Overall Survival in Peritoneal Cytology-Negative Patients
- Author
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Kubo, Hirokazu, Hiroshima, Yukihiko, Mori, Ryutaro, Saigusa, Yusuke, Murakami, Takashi, Yabushita, Yasuhiro, Sawada, Yu, Homma, Yuki, Kumamoto, Takafumi, Matsuyama, Ryusei, and Endo, Itaru
- Published
- 2019
- Full Text
- View/download PDF
44. Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R
- Author
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Miwa, Shinji, Zhang, Yong, Baek, Kyung-Eun, Uehara, Fuminari, Yano, Shuya, Yamamoto, Mako, Hiroshima, Yukihiko, Matsumoto, Yasunori, Kimura, Hiroaki, Hayashi, Katsuhiro, Yamamoto, Norio, Bouvet, Michael, Tsuchiya, Hiroyuki, Hoffman, Robert M, and Zhao, Ming
- Subjects
Cancer ,Lung ,Lung Cancer ,Emerging Infectious Diseases ,Orphan Drug ,Rare Diseases ,Animals ,Cell Line ,Tumor ,Disease Models ,Animal ,Female ,Fibrosarcoma ,Humans ,Lung Neoplasms ,Mice ,Mice ,Nude ,Neoplasm Metastasis ,Prognosis ,Salmonella typhimurium ,Sarcoma ,Xenograft Model Antitumor Assays ,HT-1080 ,orthotopic model ,nude mice ,lung metastasis ,bacterial therapy ,Oncology and Carcinogenesis - Abstract
Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor. Therefore, novel systemic therapy is needed to improve the survival of soft-tissue sarcoma. In the present study, tumor-targeting therapy with a genetically-modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated. Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. The number of lung metastasis was 8.8 ± 3.4 in the untreated group and 0.8 ± 0.8 in the treated group (P = 0.024). A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. S. typhimurium A1-R significantly reduced lung metastases and improved overall survival (P = 0.004). S. typhimurium A1-R bacterial therapy has future potential for treating advanced soft tissue sarcoma and improving prognosis of patients with lung metastasis.
- Published
- 2014
45. Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy
- Author
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Yano, Shuya, Zhang, Yong, Zhao, Ming, Hiroshima, Yukihiko, Miwa, Shinji, Uehara, Fuminari, Kishimoto, Hiroyuki, Tazawa, Hiroshi, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M
- Subjects
Cancer ,Animals ,Antineoplastic Agents ,Cell Line ,Tumor ,Humans ,Interphase ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Stomach Neoplasms ,Time-Lapse Imaging ,Xenograft Model Antitumor Assays ,cell cycle ,chemotherapy ,decoy ,FUCCI ,GFP ,RFP ,imaging ,S ,typhimurium A1-R ,tumor-targeting bacteria ,fluorescence ubiquitination-based cell cycle indicator ,typhimurium ,GFP ,RFP ,imaging ,S. typhimurium A1-R ,fluorescence ubiquitination-based cell cycle indicator ,S. typhimurium ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Time-lapse imaging demonstrated that tumor-targeting Salmonella typhimurium A1-R (A1-R) decoyed cancer cells in monolayer culture and in tumor spheres to cycle from G0/G1 to S/G2/M, as demonstrated by fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice also decoyed quiescent cancer cells, which were the majority of the cells in the tumors, to cycle from G0/G1 to S/G2/M, thereby making them sensitive to cytotoxic agents. The combination of A1-R and cisplatinum or paclitaxel reduced tumor size compared with A1-R monotherapy or cisplatinum or paclitaxel alone. The results of this study demonstrate that A1-R can decoy quiescent cancer cells to cycle to S/G2/M and sensitize them to cytotoxic chemotherapy. These results suggest a new paradigm of bacterial-decoy chemotherapy of cancer.
- Published
- 2014
46. Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) and cell line mouse models
- Author
-
Hiroshima, Yukihiko, Zhang, Yong, Murakami, Takashi, Maawy, Ali, Miwa, Shinji, Yamamoto, Mako, Yano, Shuya, Sato, Sho, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, Zhao, Ming, and Hoffman, Robert M
- Subjects
Pancreatic Cancer ,Rare Diseases ,Cancer ,Digestive Diseases ,Orphan Drug ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,5.1 Pharmaceuticals ,Angiogenesis Inhibitors ,Animals ,Cell Line ,Tumor ,Humans ,Male ,Mice ,Mice ,Nude ,Microscopy ,Confocal ,Pancreatic Neoplasms ,Real-Time Polymerase Chain Reaction ,Salmonella Infections ,Salmonella typhimurium ,Vascular Endothelial Growth Factor A ,Xenograft Model Antitumor Assays ,Pancreatic cancer ,Salmonella typhimurium A1-R ,patient-derived orthotopic xenograft ,orthotopic ,nude mice ,GFP ,VEGF ,anti-angiogenic therapy ,bevacizumab ,gemcitabine ,Oncology and Carcinogenesis - Abstract
The aim of the present study was to examine the efficacy of tumor-targeting Salmonella typhimurium A1-R treatment following anti-vascular endothelial growth factor (VEGF) therapy on VEGF-positive human pancreatic cancer. A pancreatic cancer patient-derived orthotopic xenograft (PDOX) that was VEGF-positive and an orthotopic VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) as well as a VEGF-negative cell line (Panc-1) were tested. Nude mice with these tumors were treated with gemcitabine (GEM), bevacizumab (BEV), and S. typhimurium A1-R. BEV/GEM followed by S. typhimurium A1-R significantly reduced tumor weight compared to BEV/GEM treatment alone in the PDOX and MiaPaCa-2 models. Neither treatment was as effective in the VEGF-negative model as in the VEGF-positive models. These results demonstrate that S. typhimurium A1-R following anti-angiogenic therapy is effective on pancreatic cancer including the PDOX model, suggesting its clinical potential.
- Published
- 2014
47. Fluorescence‐guided surgery improves outcome in an orthotopic osteosarcoma nude‐mouse model
- Author
-
Miwa, Shinji, Hiroshima, Yukihiko, Yano, Shuya, Zhang, Yong, Matsumoto, Yasunori, Uehara, Fuminari, Yamamoto, Mako, Kimura, Hiroaki, Hayashi, Katsuhiro, Bouvet, Michael, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Rare Diseases ,Cancer ,Animals ,Bone Neoplasms ,Cisplatin ,Disease Models ,Animal ,Female ,Fluorescence ,Lung Neoplasms ,Mice ,Nude ,Osteosarcoma ,Treatment Outcome ,osteosarcoma ,RFP ,fluorescence-guided surgery ,orthotopic mouse model ,chemotherapy ,cisplatinum ,Biomedical Engineering ,Clinical Sciences ,Human Movement and Sports Sciences ,Orthopedics - Abstract
In order to develop a model for fluorescence-guided surgery (FGS), 143B human osteosarcoma cells expressing red fluorescent protein (RFP) were injected into the intramedullary cavity of the tibia in nude mice. The fluorescent areas of residual tumors after bright-light surgery (BLS) and FGS were 10.2 ± 2.4 mm(2) and 0.1 ± 0.1 mm(2) , respectively (p
- Published
- 2014
48. Osteosarcoma Cells Enhance Angiogenesis Visualized by Color‐Coded Imaging in the In Vivo Gelfoam® Assay
- Author
-
Uehara, Fuminari, Tome, Yasunori, Miwa, Shinji, Hiroshima, Yukihiko, Yano, Shuya, Yamamoto, Mako, Mii, Sumiyuki, Maehara, Hiroki, Bouvet, Michael, Kanaya, Fuminori, and Hoffman, Robert M
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Transplantation ,Animals ,Cell Line ,Tumor ,Female ,Gelatin Sponge ,Absorbable ,Green Fluorescent Proteins ,Humans ,Implants ,Experimental ,Luminescent Proteins ,Mice ,Mice ,Nude ,Mice ,Transgenic ,Microscopy ,Confocal ,Neoplasm Transplantation ,Neovascularization ,Pathologic ,Osteosarcoma ,GREEN FLUORESCENT PROTEIN ,RED FLUORESCENT PROTEIN ,OSTEOSARCOMA ,ANGIOGENESIS ,GELFOAM ,NESTIN ,TRANSGENIC NUDE MOUSE ,CONFOCAL MICROSCOPY ,GELFOAM® ,Medical Physiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
We previously described a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In ND-GFP mice, nascent blood vessels are labeled with GFP. We report here that osteosarcoma cells promote angiogenesis in the Gelfoam® angiogenesis assay in ND-GFP mice. Gelfoam® was initially transplanted subcutaneously in the flank of transgenic ND-GFP nude mice. Seven days after transplantation of Gelfoam®, skin flaps were made and human 143B osteosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in cytoplasm were injected into the transplanted Gelfoam®. The control-group mice had only implanted Gelfoam®. Skin flaps were made at days 14, 21, and 28 after transplantation of the Gelfoam® to allow imaging of vascularization in the Gelfoam® using a variable-magnification small animal imaging system and confocal fluorescence microscopy. ND-GFP expressing nascent blood vessels penetrated and spread into the Gelfoam® in a time-dependent manner in both control and osteosarcoma-implanted mice. ND-GFP expressing blood vessels in the Gelfoam® of the osteosarcoma-implanted mice were associated with the cancer cells and larger and longer than in the Gelfoam®-only implanted mice (P
- Published
- 2014
49. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice
- Author
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Miwa, Shinji, Yano, Shuya, Zhang, Yong, Matsumoto, Yasunori, Uehara, Fuminari, Yamamoto, Mako, Hiroshima, Yukihiko, Kimura, Hiroaki, Hayashi, Katsuhiro, Yamamoto, Norio, Bouvet, Michael, Tsuchiya, Hiroyuki, Hoffman, Robert M, and Zhao, Ming
- Subjects
Cancer ,Vaccine Related ,Breast Cancer ,Prevention ,Emerging Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Bone Neoplasms ,Breast Neoplasms ,Female ,Humans ,Mice ,Mice ,Nude ,Salmonella typhimurium ,Xenograft Model Antitumor Assays ,breast cancer ,bone metastasis ,GFP ,RFP ,bacterial therapy ,Salmonella typhimurium A1-R ,Oncology and Carcinogenesis - Abstract
Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely prevented the appearance of bone metastasis of the high metastatic variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). These data indicated that S. typhimurium A1-R is useful to prevent and inhibit breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting.
- Published
- 2014
50. Effect of Portal Vein Ligation Plus Venous Congestion on Liver Regeneration in Rats
- Author
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Kawaguchi, Daisuke, Hiroshima, Yukihiko, Kumamoto, Takafumi, Mori, Ryutaro, Matsuyama, Ryusei, Ichikawa, Yasushi, Inayama, Yoshiaki, and Endo, Itaru
- Published
- 2019
- Full Text
- View/download PDF
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