31 results on '"Hoffman, Robert M"'
Search Results
2. Oncogenes and Methionine Addiction of Cancer: Role of c-MYC.
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YUSUKE AOKI, QINGHONG HAN, YUTARO KUBOTA, NORIYUKI MASAKI, OBARA, KOYA, YASUNORI TOME, BOUVET, MICHAEL, KOTARO NISHIDA, and HOFFMAN, ROBERT M.
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METHIONINE ,ONCOGENES ,WESTERN immunoblotting ,ADDICTIONS ,TUMOR growth - Abstract
Background/Aim: Methionine addiction is a general and fundamental hallmark of cancer cells, termed the Hoffman effect. Previously Vanhamme and Szpirer showed that methionine addiction could be induced by transfection of the activated HRAS1 gene to a normal cell line. In the present study, we investigated the role of the c-MYC oncogene in methionine addiction of cancer, by comparison of c-Myc expression and malignancy of methionine-addicted osteosarcoma cells and rare methionine-independent revertants, derived from the methionine-addicted cells. Materials and Methods: Methionine-independent revertant 143B osteosarcoma cells (143B-R) were derived from methionine-addicted parental 143B osteosarcoma cells (143B-P), by continuous culture in medium depleted of methionine by recombinant methioninase. To compare in vitro malignancy of methionine-addicted parental cells and methionine-independent revertant cells, the following experiments were performed: for 143B-P and 143B-R cells, cell proliferation capacity was measured with a cell-counting assay, and colony-formation capacity was determined on plastic and in soft agar, all in methionine-containing Dulbecco’s Modified Eagle’s Medium (DMEM). Tumor growth was measured in orthotopic xenograft nude-mouse models, to compare in vivo malignancy of 143B-P and 143B-R cells. c-MYC expression was examined with western immunoblotting and compared in 143BP and 143B-R cells. Results: 143B-R cells had reduced cell proliferation capacity, compared to 143B-P cells, in methionine-containing medium (p=0.003). 143B-R cells had reduced colony formation capacity on plastic (p=0.003) and in soft agar, compared to 143B-P cells in methionine-containing medium. 143B-R cells had reduced tumor growth in orthotopic xenograft nude-mouse models, compared to 143B-P cells, (p=0.002). These results demonstrate that 143B-R methionine-independent revertant cells lost malignancy. Expression of c-MYC was reduced in 143B-R methionine-independent revertant osteosarcoma cells, compared to 143B-P cells, (p=0.0007). Conclusion: The present study demonstrated that c-MYC expression is linked to malignancy and methionine addiction of cancer cells. The present study on c-MYC, and the previous study on HRAS1, suggest that oncogenes may play a role in methionine addiction, which is a hallmark of all cancers, as well as in malignancy. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Fluorescent Anti-MUC5AC Brightly Targets Pancreatic Cancer in a Patient-derived Orthotopic Xenograft.
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TURNER, MICHAEL A., HOLLANDSWORTH, HANNAH M., NISHINO, HIROTO, AMIRFAKHRI, SIAMAK, LWIN, THINZAR M., LOWY, ANDREW M., KAUR, SUKHWINDER, NATARAJAN, GOPALAKRISHNAN, MALLYA, KAVITA, HOFFMAN, ROBERT M., BATRA, SURINDER K., and BOUVET, MICHAEL
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PANCREATIC cancer ,XENOGRAFTS ,BIOMARKERS ,IMMUNOGLOBULINS ,TUMOR growth ,ANIMAL models in research - Abstract
Background: Overexpression of mucin-5AC (MUC5AC) makes it a targetable biomarker in pancreatic cancer. The present study evaluated tumor targeting with a MUC5AC antibody conjugated to a near-infrared dye in a patient-derived orthotopic xenograft (PDOX) mouse model. Materials and Methods: MUC5AC monoclonal antibody was conjugated to the near-infrared dye IRDye800CW to synthesize MUC5AC-IR800. PDOX models were established by implanting a high-MUC5AC-expressing patient-derived pancreatic tumor on the pancreas of nude mice. After 4 weeks of PDOX tumor growth, mice were imaged after receiving MUC5AC-IR800 (75 μg) intravenously. Results: In the PDOX models, MUC5AC-IR800 selectively and brightly targeted the pancreatic tumor (tumor to background ratio: 2.46±0.465). Conclusion: MUC5AC-IR800 provides distinct visualization of pancreatic tumors. MUC5AC-IR800 may be used clinically in the future to improve pancreatic cancer resection. This novel fluorescent probe is also promising for targeting of pre-malignant pancreatic lesions with subsequent resection under fluorescence guidance. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Multikinase-Inhibitor Screening in Drug-resistant Osteosarcoma Patient-derived Orthotopic Xenograft Mouse Models Identifies the Clinical Potential of Regorafenib.
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TAKASHI HIGUCHI, KENTARO IGARASHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, BOUVET, MICHAEL, HIROYUKI TSUCHIYA, and HOFFMAN, ROBERT M.
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LABORATORY mice ,OSTEOSARCOMA ,REGORAFENIB ,TUMOR growth ,SORAFENIB - Abstract
Background/Aim: Osteosarcoma is a recalcitrant heterogenous malignancy. The aim of the present study was to compare a series of multikinase inhibitors (MKIs) for efficacy on two drug-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) models in order to identify a clinical candidate. Materials and Methods: The two osteosarcoma PDOX models were tested for response to the following MKIs: pazopanib, sunitinib, sorafenib, crizotinib, and regorafenib, in comparison to first-line treatment with cisplatinum and an untreated control. Results: Regorafenib led to regression of osteosarcoma in both PDOXs. Total necrosis was observed pathologically in the regorafenib-treated tumors. Sorafenib arrested growth, without inducing regression, in one osteosarcoma model but not the other, and the other MKIs only slowed tumor growth. Conclusion: The present study demonstrated that regorafenib is much more effective than the other MKIs tested and has clinical potential against recalcitrant osteosarcoma. [ABSTRACT FROM AUTHOR]
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- 2021
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5. Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor
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An, Zili, Wang, Xiaoen, Willmott, Neville, Chander, Surinder K., Tickle, Simon, Docherty, Andrew J. P., Mountain, Andrew, Millican, Andrew T., Morphy, Richard, Porter, John R., Ola Epemolu, R., Kubota, Tetsuro, Moossa, A. R., and Hoffman, Robert M.
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- 1997
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6. Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
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Sugisawa, Norihiko, Higuchi, Takashi, Han, Qinghong, Hozumi, Chihiro, Yamamoto, Jun, Tashiro, Yoshihiko, Nishino, Hiroto, Kawaguchi, Kei, Bouvet, Michael, Murata, Takuya, Unno, Michiaki, and Hoffman, Robert M.
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PACLITAXEL ,CELL growth ,INJECTIONS ,TUMOR growth ,CANCER treatment ,CANCER chemotherapy ,BIOLOGICAL models ,RESEARCH ,OVARIAN tumors ,XENOGRAFTS ,ANIMAL experimentation ,ANTHROPOMETRY ,RESEARCH methodology ,ANTINEOPLASTIC agents ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,ENZYMES ,SARCOMA ,RECOMBINANT proteins ,DRUG resistance in cancer cells ,MICE ,PHARMACODYNAMICS - Abstract
Purpose: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX).Methods: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks.Results: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93).Conclusion: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy. [ABSTRACT FROM AUTHOR]- Published
- 2021
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7. Eribulin Regresses a Doxorubicin-resistant Dedifferentiated Liposarcoma in a Patient-derived Orthotopic Xenograft Mouse Model.
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KENTARO IGARASHI, KEI KAWAGUCHI, TASUKU KIYUNA, KENTARO MIYAKE, TAKASHI HIGUCHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, SINGH, SHREE RAM, HIROYUKI TSUCHIYA, and HOFFMAN, ROBERT M.
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LIPOSARCOMA ,ERIBULIN ,TUMOR growth ,DRUG efficacy ,BODY weight ,MICE - Abstract
Background/Aim: Dedifferentiated liposarcoma (DDLPS) is recalcitrant type of sarcoma. DDLPS has a low survival rate with high recurrence and metastasis. In the present study, we evaluated the efficacy of several drugs against doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model for precision oncology. To establish the PDOX model, a tumor from a patient who had recurrent high-grade DDLPS from the retroperitoneum was previously grown orthotopically in the retroperitoneum of nude mice. Materials and Methods: We randomized DDLPS PDOX models into 8 treatment groups when tumor volume became approximately 100 mm3: control, no treatment; G2, doxorubicin (DOX); G3, pazopanib (PAZ); G4, gemcitabine (GEM) combined with docetaxel (DOC); G5, trabectedin (YON); G6, temozolomide (TEM); G7, palbociclib (PAL); G8, eribulin (ERB). Tumor length and width were measured both at the beginning and at the end of treatment. Results: At the end of treatment (day 14), all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control, except DOX. ERB was significantly more effective and regressed tumor volume compared to other treatments on day 14 after initiation of treatment. No significant differences were found in the relative body weight on day 14 compared to day 0 in any group. Conclusion: The clinical potential of ERB against DDLPS is herein presented in a PDOX model. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Near-infrared photoimmunotherapy is effective treatment for colorectal cancer in orthotopic nude-mouse models.
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Hollandsworth, Hannah M., Amirfakhri, Siamak, Filemoni, Filemoni, Molnar, Justin, Hoffman, Robert M., Yazaki, Paul, and Bouvet, Michael
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COLORECTAL cancer ,SURGICAL excision ,TUMOR growth ,CELL death ,CANCER treatment ,DENDRITIC cells ,ADENOMATOUS polyps - Abstract
Background: Photoimmunotherapy (PIT) employs the use of a near-infrared (NIR) laser to activate an antibody conjugated to a NIR-activatable dye to induce cancer cell death. PIT has shown to be effective in a number of studies, however, there are no data on its use in colorectal cancer in an orthotopic model. Methods: Humanized anti-CEA antibody (M5A) was conjugated to NIR-activatable IRDye700DX (M5A-700). PIT was validated in vitro with a colon cancer cell-line, using a laser intensity of either 4 J/cm
2 , 8 J/cm2 , or 16 J/cm2 . Orthotopic colon cancer mouse models were established by surgical implantation of LS174T tumor fragments onto the cecum. M5A-700 was administered and PIT was performed 24 hours later using a 690 nm laser. Repeat PIT was performed after 7 days in one group. Control mice received laser treatment only. Results: In vitro PIT demonstrated tumor cell death in a laser intensity dose-dependent fashion. In orthotopic models, control mice demonstrated persistent tumor growth. Mice that underwent PIT one time had tumor growth arrested for one week, after which re-growth occurred. The group that received repeated PIT exposure had persistent inhibition of tumor growth. Conclusion: PIT arrests tumor growth in colon cancer orthotopic nude-mouse models. Repeated PIT arrests colon cancer growth for a longer period of time. PIT may be a useful therapy in the future as an adjunct to surgical resection or as primary therapy to suppress tumor progression. [ABSTRACT FROM AUTHOR]- Published
- 2020
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9. A Novel Anionic-phosphate-platinum Complex Effectively Targets a Cisplatinum-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model.
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KENTARO IGARASHI, KEI KAWAGUCHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, TAKASHI HIGUCHI, YUTA TANIGUCHI, HIROTAKA YONEZAWA, YOSHIHIRO ARAKI, SEI MORINAGA, SWETA MISRA, NELSON, SCOTT D., DRY, SARAH M., YUNFENG LI, AKIRA ODANI, SINGH, SHREE RAM, HIROYUKI TSUCHIYA, and HOFFMAN, ROBERT M.
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OSTEOSARCOMA ,BODY size ,TUMOR growth ,XENOGRAFTS ,PLATINUM compounds ,MICE ,HYPERPHOSPHATEMIA - Abstract
Background/Aim: We have previously developed a novel bone-targeting platinum compound, 3Pt, and showed that it has strong inhibitory activity against osteosarcoma cells and orthotopic cell-line xenograft mouse models. In the present report, we compared the efficacy of 3Pt to cisplatinum (CDDP) in a CDDP-resistant relapsed osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Patients and Methods: The tumor of a patient with osteosarcoma of the distal femur was treated with CDDP-based chemotherapy followed by surgery. The surgical specimen was used to establish a PDOX model. An osteosarcoma cell line was also established from the original patient tumor. Osteosarcoma cell viability was assessed with the WST-8 assay and the IC50 values were calculated. The PDOX models were randomized into three groups: untreated control, CDDP-treated group, and 3Pt-treated group. Tumor size and body weight were measured twice a week. Results: 3Pt had a strong concentration-dependent cytocidal effect in vitro. The IC50 value of 3Pt was significantly lower than that of CDDP. On day 14 of the treatment, 3Pt caused a significantly greater tumor growth inhibition compared to the untreated control and CDDP-treated mice. Conclusion: 3Pt is a promising clinical candidate for the treatment of recalcitrant osteosarcoma. [ABSTRACT FROM AUTHOR]
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- 2020
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10. Pazopanib Inhibits Tumor Growth, Lymph-node Metastasis and Lymphangiogenesis of an Orthotopic Mouse of Colorectal Cancer.
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GUANGWEI ZHU, MING ZHAO, QINGHONG HAN, YUYING TAN, YU SUN, BOUVET, MICHAEL, SINGH, SHREE RAM, JIANXIN YE, and HOFFMAN, ROBERT M.
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COLORECTAL cancer ,LYMPHATIC metastasis ,TUMOR growth ,LYMPH node cancer ,REGULATION of body weight ,METASTASIS - Abstract
Background/Aim: Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The aim of the present study was to determine the efficacy of PAZ on tumor growth, lymph node metastasis and lymphangiogenesis in an orthotopic nude mouse model in colorectal cancer. Materials and Methods: CT-26-green fluorescence protein (GFP)- expressing mouse colon cancer cells were injected into nude mice to establish a subcutaneous colorectal cancer model and were treated with saline and PAZ. Additionals subcutaneous tumors were harvested and cut into 5 mm³ fragments, then tumor fragments were implanted orthotopically in the cecum to establish an orthotopic colorectal-cancer nude mouse model. Orthotopic mice were randomized into two groups for the treatment with saline and PAZ, respectively. Tumor width, length and mouse body weight was measured twice a week. The Fluor Vivo imaging system was used to image the GFP. Hematoxylin & eosin staining and immunohistochemical staining was used for histological analysis. Results: PAZ inhibited the growth of subcutaneous colorectal cancer, as wells as orthotopic transplanted colorectal cancer tumors. PAZ suppressed lymph node metastasis and lymphangiogenesis in the orthotopic colon cancer model. No significant changes were observed in the body weight between the control and the mice treated with PAZ. Conclusion: PAZ can inhibit the growth of colorectal cancer and inhibit lymph node metastasis and lymphangiogenesis in orthotopic colon cancer nude mouse models. [ABSTRACT FROM AUTHOR]
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- 2020
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11. The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model.
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Higuchi, Takashi, Sugisawa, Norihiko, Yamamoto, Jun, Oshiro, Hiromichi, Han, Qinghong, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Tan, Yuying, Kuchipudi, Shreya, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M.
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BODY size ,METHIONINE ,TUMOR growth ,DNA methylation ,TUMOR treatment ,BODY weight ,DOXORUBICIN ,ANTHRACYCLINES ,THERAPEUTIC use of antineoplastic agents ,BIOLOGICAL models ,XENOGRAFTS ,OSTEOSARCOMA ,ANTHROPOMETRY ,ANTINEOPLASTIC agents ,AZACITIDINE ,BONE tumors ,ENZYMES ,COMBINED modality therapy ,DRUG resistance in cancer cells ,MICE ,ANIMALS ,PHARMACODYNAMICS - Abstract
Purpose: Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.Methods: The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment.Results: We found that tumor growth was arrested only by the o-rMETase-AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change.Conclusion: This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma. [ABSTRACT FROM AUTHOR]- Published
- 2020
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12. PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model.
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TAKASHI HIGUCHI, JUN YAMAMOTO, NORIHIKO SUGISAWA, YOSHIHIKO TASHIRO, HIROTO NISHINO, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, BOUVET, MICHAEL, SINGH, SHREE RAM, HIROYUKI TSUCHIYA, and HOFFMAN, ROBERT M.
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NUCLEAR receptors (Biochemistry) ,OSTEOSARCOMA ,PEROXISOME proliferator-activated receptors ,BODY size ,TUMOR growth ,CANCER cell differentiation ,HORMONE receptor positive breast cancer - Abstract
Background/Aim: Cisplatinum (CDDP) is a firstline drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. Materials and Methods: In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Results: Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 µmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. Conclusion: These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil regressed a colon cancer growing on the peritoneal surface in a patient-derived orthotopic xenograft mouse model.
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Park, Jun Ho, Han, Qinghong, Zhao, Ming, Tan, Yuying, Higuchi, Takashi, Yoon, Sang Nam, Sugisawa, Norihiko, Yamamoto, Jun, Bouvet, Michael, Clary, Bryan, Singh, Shree Ram, and Hoffman, Robert M.
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COLON cancer ,PERITONEAL cancer ,RECOMBINANT drugs ,TUMOR growth ,METASTASIS ,MICE ,DRUG control - Abstract
• Colorectal cancer is the third most common cancer worldwide. • The peritoneal surface is a common site of metastasis in colorectal cancer. • The combination of 5-FU + OXA + o-rMETase was efficacious for colon cancer peritoneal metastasis. • First study to show o-rMETase inhibits peritoneal metastases. • o-rMETase is promising as a novel cancer therapeutic for human colon cancer. The aim of this study was to determine the efficacy of oral recombinant methioninase (o-rMETase) on a model of colon cancer growing on the peritoneal surface using a patients-derived orthotopic xenograft (PDOX) nude mouse model. Forty PDOX mouse models with colon cancer growing on the peritoneum were divided into 4 groups of 10 mice each by measuring the tumor size and fluorescence intensity: untreated control; 5-fluorouracil (5-FU) (50 mg/kg, once a week for two weeks, ip) and oxaliplatinum (OXA) (6 mg/kg, once a week for two weeks, ip); o-rMETase (100 units/day, oral 14 consecutive days); combination 5-FU + OXA and o-rMETase. All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA plus o-rMETase was significantly more efficacious than the control and each drug alone and was the only treatment that caused tumor regression. The present study is the first demonstrating the efficacy of o-rMETase combination therapy on a PDOX model of peritoneal colon cancer, suggesting potential clinical development of o-rMETase in a recalcitrant cancer. [ABSTRACT FROM AUTHOR]
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- 2019
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14. Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model.
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Miyake, Kentaro, Murata, Takuya, Murakami, Takashi, Zhao, Ming, Kiyuna, Tasuku, Kawaguchi, Kei, Igarashi, Kentaro, Miyake, Masuyo, Lwin, Thinzar M., Hozumi, Chihiro, Komatsu, Shin, Kikuchi, Takashi, Bouvet, Michael, Shimoya, Koichiro, Singh, Shree Ram, Endo, Itaru, and Hoffman, Robert M.
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SALMONELLA typhimurium ,CERVICAL cancer ,DRUG resistance in cancer cells ,CERVIX uteri ,CERVIX uteri diseases ,TUMOR growth ,ANIMAL experimentation ,ANIMALS ,BIOLOGICAL models ,DOXORUBICIN ,MICE ,OLIGOPEPTIDES ,PACLITAXEL ,SALMONELLA ,CERVIX uteri tumors ,ALBUMINS ,PHARMACODYNAMICS - Abstract
Purpose: Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model.Methods: Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week.Results: Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively).Conclusions: Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer. [ABSTRACT FROM AUTHOR]- Published
- 2019
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15. The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model.
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Higuchi, Takashi, Miyake, Kentaro, Sugisawa, Norihiko, Oshiro, Hiromichi, Zhang, Zhiying, Razmjooei, Sahar, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M.
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PLATELET-derived growth factor receptors ,SARCOMA ,BODY size ,STRIATED muscle ,TUMOR growth ,MONOCLONAL antibodies - Abstract
Purpose: Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX).Methods: Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment.Results: Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis.Conclusions: The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma. [ABSTRACT FROM AUTHOR]- Published
- 2019
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16. Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice.
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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.
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SOFT tissue tumors ,SALMONELLA typhimurium ,TUMOR growth ,LABORATORY mice ,PROTEIN-tyrosine kinase inhibitors ,TUMOR treatment - 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. [ABSTRACT FROM AUTHOR]- Published
- 2015
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17. The Tumor-Educated-Macrophage Increase of Malignancy of Human Pancreatic Cancer Is Prevented by Zoledronic Acid.
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Hiroshima, Yukihiko, Maawy, Ali, Hassanein, Mohamed K., Menen, Rhiana, Momiyama, Masashi, Murakami, Takashi, Miwa, Shinji, Yamamoto, Mako, Uehara, Fuminari, Yano, Shuya, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M.
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PANCREATIC cancer ,MACROPHAGES ,ZOLEDRONIC acid ,TUMOR growth ,LABORATORY mice ,CANCER cell culture ,CANCER cell proliferation ,PREVENTION ,THERAPEUTICS - Abstract
We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as “tumor-educated-macrophages” (Edu) and macrophages harvested from mice without tumors as “naïve-macrophages” (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
18. Development of a Clinically-Precise Mouse Model of Rectal Cancer.
- Author
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Kishimoto, Hiroyuki, Momiyama, Masashi, Aki, Ryoichi, Kimura, Hiroaki, Suetsugu, Atsushi, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M.
- Subjects
RECTAL cancer ,TUMOR growth ,LABORATORY mice ,TUMORS ,CANCER cells ,EPITHELIAL cells ,MATHEMATICAL models - Abstract
Currently-used rodent tumor models, including transgenic tumor models, or subcutaneously growing tumors in mice, do not sufficiently represent clinical cancer. We report here development of methods to obtain a highly clinically-accurate rectal cancer model. This model was established by intrarectal transplantation of mouse rectal cancer cells, stably expressing green fluorescent protein (GFP), followed by disrupting the epithelial cell layer of the rectal mucosa by instilling an acetic acid solution. Early-stage tumor was detected in the rectal mucosa by 6 days after transplantation. The tumor then became invasive into the submucosal tissue. The tumor incidence was 100% and mean volume (±SD) was 1232.4 ± 994.7 mm
3 at 4 weeks after transplantation detected by fluorescence imaging. Spontaneous lymph node metastasis and lung metastasis were also found approximately 4 weeks after transplantation in over 90% of mice. This rectal tumor model precisely mimics the natural history of rectal cancer and can be used to study early tumor development, metastasis, and discovery and evaluation of novel therapeutics for this treatment-resistant disease. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
19. The cancer-inhibitory effects of proliferating tumor-residing fibroblasts.
- Author
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Delinassios, John G. and Hoffman, Robert M.
- Subjects
- *
FIBROBLASTS , *CANCER cell growth , *EXTRACELLULAR matrix , *CANCER cells , *WOUND healing , *TUMOR growth - Abstract
Initiation, local progression, and metastasis of cancer are associated with specific morphological, molecular, and functional changes in the extracellular matrix and the fibroblasts within the tumor microenvironment (TME). In the early stages of tumor development, fibroblasts are an obstacle that cancer cells must surpass or nullify to progress. Thus, in early tumor progression, specific signaling from cancer cells activates bio-pathways, which abolish the innate anticancer properties of fibroblasts and convert a high proportion of them to tumor-promoting cancer-associated fibroblasts (CAFs). Following this initial event, a wide spectrum of gene expression changes gradually leads to the development of a stromal fibroblast population with complex heterogeneity, creating fibroblast subtypes with characteristic profiles, which may alternate between being tumor-promotive and tumor-suppressive, topologically and chronologically in the TME. These fibroblast subtypes form the tumor's histological landscape comprising areas of cancer growth, inflammation, angiogenesis, invasion fronts, proliferating and non-proliferating fibroblasts, cancer-cell apoptosis, fibroblast apoptosis, and necrosis. These features reflect general deregulation of tissue homeostasis within the TME. This review discusses fundamental and current knowledge that has established the existence of anticancer fibroblasts within the various interacting elements of the TME. It is proposed that the maintenance of fibroblast proliferation is an essential parameter for the activation of their anticancer capacity, similar to that by which normal fibroblasts would be activated in wound repair, thus maintaining tissue homeostasis. Encouragement of research in this direction may render new means of cancer therapy and a greater understanding of tumor progression. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
20. Involvement of CXCR4 Chemokine Receptor in Metastastic HER2-Positive Esophageal Cancer.
- Author
-
Gros, Stephanie J., Kurschat, Nina, Drenckhan, Astrid, Dohrmann, Thorsten, Forberich, Evelyn, Effenberger, Katharina, Reichelt, Uta, Hoffman, Robert M., Pantel, Klaus, Kaifi, Jussuf T., Izbicki, Jakob R., and Ming Tan
- Subjects
ESOPHAGEAL cancer ,CHEMOKINE receptors ,TUMOR growth ,TRASTUZUMAB ,METASTASIS ,CANCER - Abstract
A functional linkage of the structurally unrelated receptors HER2 and CXCR4 has been suggested for breast cancer but has not been evaluated for esophageal carcinoma. The inhibition of HER2 leads to a reduction of primary tumor growth and metastases in an orthotopic model of esophageal carcinoma. The chemokine receptor CXCR4 has been implicated in metastatic dissemination of various tumors and correlates with poor survival in esophageal carcinoma. The aim of this study was to investigate a correlation between the expression levels of HER2 and CXCR4 and to evaluate the involvemnent of CXCR4-expression in HER2-positive esophageal carcinoma. The effects of HER2-inhibition with trastuzumab and of CXCR4- inhibition with AMD3100 on primary tumor growth, metastatic homing, and receptor expression were evaluated in vitro and in an orthotopic model of metastatic esophageal carcinoma using MRI for imaging. The clinical relevance of HER2- and CXCR4-expression was examined in esophageal carcinoma patients. A significant correlation of HER2- and CXCR4- expression in primary tumor and metastases exists in the orthotopic model. Trastuzumab and AMD3100 treatment led to a significant reduction of primary tumor growth, metastases and micrometastases. HER2-expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases. The positive correlation between HER2- and CXCR4-expression was validated in esophageal cancer patients. The correlation of CXCR4- and HER2-expression and the elevation of HER2-expression and reduction of metastases through CXCR4-inhibition suggest a possible functional linkage and a role in tumor dissemination in HER2-positive esophageal carcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
21. Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF.
- Author
-
Murphy, Eric A., Shields, David J., Stoletov, Konstantin, Dneprovskaia, Elena, McElroy3, Michele, Greenberg, Joshua I., Lindquist, Jeff, Acevedo, Lisette M., Anand, Sudarshan, Majeti, Bharat Kumar, Tsigelny, lgor, Saldanha, Adrian, Walsh, Breda, Hoffman, Robert M., Bouvet, Michael, Klemke, Richard L., Vogt, Peter K., Arnold, Lee, Wrasidlo, Wolfgang, and Cheresh, David A.
- Subjects
TUMOR growth ,NEOVASCULARIZATION ,CANCER cell proliferation ,HIGH throughput screening (Drug development) ,PHARMACOKINETICS ,ALLOSTERIC regulation ,THERAPEUTICS - Abstract
Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained aminotriazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRβ and BRAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg (fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFR and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and munne models of angiogenesis, and a combination of previously characterized PDGFRβ and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murme orthotopic tumors in both the kidney and pancreas. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
22. Green fluorescent protein imaging of tumour growth, metastasis, and angiogenesis in mouse models
- Author
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Hoffman, Robert M
- Subjects
- *
TUMOR growth , *METASTASIS , *CANCER cells , *GREEN fluorescent protein - Abstract
We have developed a way of imaging metastases in mice by use of tumour cells expressing green fluorescent protein (GFP) that can be used to examine fresh tissue, both in situ and externally. These mice present many new possibilities for research including real-time studies of tumour progression, metastasis, and drug–response evaluations. We have now also introduced the GFP gene, cloned from bioluminescent organisms, into a series of human and rodent cancer-cell lines in vitro, which stably express GFP after transplantation to rodents with metastatic cancer. Techniques were also developed for transduction of tumours by GFP in vivo. With this fluorescent tool, single cells from tumours and metastases can be imaged. GFP-expressing tumours of the colon, prostate, breast, brain, liver, lymph nodes, lung, pancreas, bone, and other organs have also been visualised externally by use of quantitative transcutaneous whole-body fluorescence imaging. GFP technology has also been used for real-time imaging and quantification of angiogenesis. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
23. Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.
- Author
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Miyake, Masuyo, Miyake, Kentaro, Han, Qinghong, Igarashi, Kentaro, Kawaguchi, Kei, Barangi, Maryam, Kiyuna, Tasuku, Sugisawa, Norihiko, Higuchi, Takashi, Oshiro, Hiromichi, Zhang, Zhiying, Razmjooei, Sahar, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M.
- Subjects
- *
STOMACH cancer , *FLUOROURACIL , *CANCER chemotherapy , *CELL cycle , *TUMOR growth , *CANCER cells , *ORAL mucosa - Abstract
Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G 2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic. • Methionine addiction is a fundamental and general hallmark of cancer. • Methionine restriction arrests the cell cycle of cancer cells in the S/G2 phase. • Oral recombinant methioninase shows synergy with 5-fluorouracil on poorly differentiated gastric cancer cells. • Oral recombinant methioninase has clinical potential for treating gastric cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
24. Tumor Growth Control with IDO-Silencing Salmonella—Letter.
- Author
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Hoffman, Robert M.
- Subjects
- *
SALMONELLA typhimurium , *TUMOR growth - Abstract
A letter to the editor is presented in response to the article "Systemic Delivery of Salmonella typhimurium Transformed with IDO shRNA Enhances Intratumoral Vector Colonization and Suppresses Tumor Growth," by C. A. Blanche, E. R. Manuel, T. I. Kaltcheva, A. N. Wong, J. D. I. Ellenhom and B. R. Blazar, in the 2012 issue.
- Published
- 2013
- Full Text
- View/download PDF
25. Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model.
- Author
-
Higuchi, Takashi, Han, Qinghong, Miyake, Kentaro, Oshiro, Hiromichi, Sugisawa, Norihiko, Tan, Yuying, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M.
- Subjects
- *
SARCOMA , *METHIONINE , *BODY size , *TUMOR growth , *DNA methylation , *DOXORUBICIN , *ANTHRACYCLINES - Abstract
Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise. • Cancer cells are methionine (MET) and methylation addicted. • Oral rMETase (o-rMETase) is efficacious in cancers grown in patient-derived orthotopic xenograft (PDOX) models. • Combination of o-rMETase and DAC arrests undifferentiated-soft tissue sarcoma (USTS) USTS-PDOX. • Tumor treated with o-rMETase-DAC combination show tumor necrosis with degenerative changes. • Efficacy of o-rMETase-DAC combination on USTS PDOX tumor show clinical promise. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
26. Efficacy of oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil on primary colon cancer in a patient-derived orthotopic xenograft mouse model.
- Author
-
Park, Jun Ho, Zhao, Ming, Han, Qinghong, Sun, Yu, Higuchi, Takashi, Sugisawa, Norihiko, Yamamoto, Jun, Singh, Shree Ram, Clary, Bryan, Bouvet, Michael, and Hoffman, Robert M.
- Subjects
- *
COLON cancer , *TUMOR growth , *RECOMBINANT drugs , *MICE , *FLUOROURACIL , *FLUORESCENT proteins , *TUMOR treatment - Abstract
The aim of this study was to determine the efficacy of oral recombinant methioninase (o -rMETase) on a colon cancer primary tumor using a patient-derived orthotopic xenograft (PDOX) nude mouse model. Forty colon cancer primary tumor PDOX mouse models were divided into 4 groups of 10 mice each (total 40 mice) by measuring the tumor size. The groups were as follows: untreated control; 5-fluorouracil (5-FU) (50 mg/kg, once a week for two weeks, N = 10 mice) and oxaliplatinum (OXA) (6 mg/kg, once a week for two weeks, N = 10 mice); o -rMETase (100 units/day, oral 14 consecutive days, N = 10 mice); combination of 5-FU + OXA and o -rMETase (N = 10 mice). All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA and o -rMETase was significantly more efficacious than other treatments. The present study demonstrates the efficacy of o -rMETase combination therapy on a PDOX colon cancer primary tumor, suggesting potential clinical development of o -rMETase in recalcitrant cancer. • Colorectal cancer is the third most common cancer. • Demonstrated the efficacy of o -rMETase in a PDOX primary colon cancer model. • 5-FU + OXA and o -rMETase combination was more efficacious. • Potential clinical development of o -rMETase in recalcitrant cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
27. Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model.
- Author
-
Higuchi, Takashi, Miyake, Kentaro, Oshiro, Hiromichi, Sugisawa, Norihiko, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Chawla, Sant P., Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M.
- Subjects
- *
EWING'S sarcoma , *OSTEOSARCOMA , *BODY size , *BONE cancer , *TUMOR growth , *HYPERTONIC saline solutions - Abstract
Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma. • Osteosarcoma is the most common primary malignant bone tumor. • Osteosarcoma shows resistance to mainly available drugs. • Trabectedin (TRAB) and irinotecan (IRT) combination can regress osteosarcoma PDOX. • First study shows TRAB-IRT combination is active in osteosarcoma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
28. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice.
- Author
-
Kioi, Mitomu, Vogel, Hannes, Schultz, Geoffrey, Hoffman, Robert M., Harsh, Griffith R., and Brown, J. Martin
- Subjects
- *
GLIOBLASTOMA multiforme , *RADIOTHERAPY , *RADIATION , *BONE marrow cells , *NEOVASCULARIZATION , *TUMOR growth , *LABORATORY mice , *PATIENTS , *BRAIN tumor treatment , *GLIOMA treatment , *PROTEIN metabolism , *ANIMAL experimentation , *ANTIGENS , *ANTINEOPLASTIC agents , *BONE marrow , *BRAIN tumors , *CELL lines , *CANCER relapse , *CELL receptors , *CELL motility , *COMPARATIVE studies , *CYTOKINES , *GLIOMAS , *IMMUNOGLOBULINS , *HETEROCYCLIC compounds , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MONOCYTES , *RESEARCH , *RESEARCH funding , *XENOGRAFTS , *EVALUATION research , *ANTI-HIV agents , *PATHOLOGIC neovascularization , *PHARMACODYNAMICS , *METABOLISM , *PHYSIOLOGICAL effects of radiation , *CANCER treatment - Abstract
Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
29. A Novel Alkylating Agent, Glufosfamide, Enhances the Activity of Gemcitabine In Vitro and In Vivo.
- Author
-
Ammons, W. Steve, Jin-Wei Wang, Zhijian Yang, Tidmarsh, George F., and Hoffman, Robert M.
- Subjects
- *
ALKYLATING agents , *CANCER cell growth , *PANCREATIC cancer , *PANCREATIC acinar cells , *APOPTOSIS , *TUMOR growth , *LABORATORY mice - Abstract
Glufosfamide is an alkylating agent consisting of iphosphoramide mustard conjugated to glucose that is currently included in clinical studies of pancreatic cancer. We studied the effects of glufosfamide, in combination with gemcitabine, on in vitro and in vivo models of pancreatic cancer. In proliferation assays, glufosfamide and gemcitabine inhibited the growth of MiaPaCa- 2, H766t, and PANC-1 cells, but the combination of the two agents provided greater effects. Apoptosis of MiaPaCa-2 cells, measured by fluorescence-activated cell sorting, was enhanced by the combination of the two drugs, compared to single-agent treatment. Glufosfamide alone inhibited the growth of red fluorescent protein-- expressing MiaPaCa-2 tumors in an orthotopic nude mouse model in a dose-dependent manner. Combining glufosfamide (30 mg/kg) with gemcitabine resulted in enhanced inhibition of tumor growth and significantly prolonged survival. Immunohistochemistry of excised tumors revealed that both glufosfamide and gemcitabine increased levels of apoptosis (measured by terminal deoxynucleotidyl transferase--mediated nick end labeling staining) and reduced proliferation (measured by proliferating cell nuclear antigen staining). No effects on microvessel density were observed. These results support the use of the alkylating agent glufosfamide and the DNA synthesis inhibitor gemcitabine, rather than the use of either agent alone, to provide greater benefits and demonstrate that this combination treatment should be useful in the clinical treatment of pancreatic carcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
30. Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression.
- Author
-
Higuchi, Takashi, Sugisawa, Norihiko, Miyake, Kentaro, Oshiro, Hiromichi, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Kline, Zoey, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M.
- Subjects
- *
BODY size , *ANIMAL mortality , *TUMOR growth , *P-glycoprotein , *MULTIDRUG resistance - Abstract
• PPARγ agonist pioglitazone reverses DOX-resistance in osteosarcoma PDOX. • Pioglitazone modulate P-glycoprotein and overcome DOX-resistance in osteosarcoma PDOX. • DOX-Pioglitazone combination arrests DOX-resistance osteosarcoma PDOX. • No significant body weight loss or animal deaths seen after Pioglitazone treatment. Multidrug resistance (MDR) which results in chemoresistance is a major problem in osteosarcoma. P-glycoprotein (P-gp) plays a critical role in MDR by pumping out chemotherapy agents. Peroxisome proliferator activated receptor gamma (PPARγ) is a nuclear receptor involved in cellular differentiation and proliferation. Recently, a correlation between the expression and activity of PPARγ and the expression of P-gp-associated with MDR, has been reported in several human cancers. The present study determined if pioglitazone (PIO), a PPARγ agonist, could modulate P-gp and overcome doxorubicin (DOX)-resistance in a patient-derived orthotopic xenograft (PDOX) model of osteosarcoma. P-gp mRNA expression was quantified in 143B human osteosarcoma cells treated with DOX with/without PIO. The osteosarcoma PDOX models were randomized into four treatment groups of six mice: Control; PIO alone; DOX alone; DOX and PIO combination. Tumor size and body weight were measured during the 14 days of treatment. DOX significantly induced P-gp mRNA in a dose-dependent manner in 143B cells. PIO inhibited the increase of P-gp mRNA induced by DOX treatment when co-administrated with DOX. Tumor growth was inhibited the most by the DOX-PIO combination. Tumors treated with the DOX-PIO combination also had the most tumor necrosis. This study suggests that the DOX-PIO combination could be used in the clinic for osteosarcoma patients who develop DOX-resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
31. The combination of gemcitabine and docetaxel arrests a doxorubicin-resistant dedifferentiated liposarcoma in a patient-derived orthotopic xenograft model.
- Author
-
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.
- Subjects
- *
LIPOSARCOMA , *TUMOR growth , *BODY weight - Abstract
• Liposarcoma (LS) is a chemotherapy-resistant disease. • Developed dedifferentiated liposarcoma (DDLS) patient-derived orthotopic xenograft (PDOX) model. • Gemcitabine (GEM) combined with docetaxel (DOC) arrested the tumor growth of DDLS PDOX. • GEM combined with DOC has clinical potential for this and possibly other DDLS patients. Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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