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Hassan, B. B., S. M. Elshafae, W. Supsavhad, J. K. Simmons, W. P. Dirksen, S. M. Sokkar y T. J. Rosol. "Feline Mammary Cancer". Veterinary Pathology 54, n.º 1 (11 de julio de 2016): 32–43. http://dx.doi.org/10.1177/0300985816650243.
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Feline mammary carcinoma (FMC) is similar to human breast cancer in the late age of onset, incidence, histopathologic features, biological behavior, and pattern of metastasis. Therefore, FMC has been proposed as a relevant model for aggressive human breast cancer. The goals of this study were to develop a nude mouse model of FMC tumor growth and metastasis and to measure the expression of genes responsible for lymphangiogenesis, angiogenesis, tumor progression, and lymph node metastasis in FMC tissues and cell lines. Two primary FMC tissues were injected subcutaneously, and 6 FMC cell lines were injected into 3 sites (subcutaneous, intratibial, and intracardiac) in nude mice. Tumors and metastases were monitored using bioluminescent imaging and characterized by gross necropsy, radiology, and histopathology. Molecular characterization of invasion and metastasis genes in FMC was conducted using quantitative real-time reverse transcription polymerase chain reaction in 6 primary FMC tissues, 2 subcutaneous FMC xenografts, and 6 FMC cell lines. The histologic appearance of the subcutaneous xenografts resembled the primary tumors. No metastasis was evident following subcutaneous injection of tumor tissues and cell lines, whereas lung, brain, liver, kidney, eye, and bone metastases were confirmed following intratibial and intracardiac injection of FMC cell lines. Finally, 15 genes were differentially expressed in the FMC tissues and cell lines. The highly expressed genes in all samples were PDGFA, PDGFB, PDGFC, FGF2, EGFR, ERBB2, ERBB3, VEGFD, VEGFR3, and MYOF. Three genes ( PDGFD, ANGPT2, and VEGFC) were confirmed to be of stromal origin. This investigation demonstrated the usefulness of nude mouse models of experimental FMC and identified molecular targets of FMC progression and metastasis.
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Hassan, Bardes B., Lucas A. Altstadt, Wessel P. Dirksen, Said M. Elshafae y Thomas J. Rosol. "Canine Thyroid Cancer: Molecular Characterization and Cell Line Growth in Nude Mice". Veterinary Pathology 57, n.º 2 (21 de febrero de 2020): 227–40. http://dx.doi.org/10.1177/0300985819901120.
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Thyroid cancer is the most common endocrine malignancy in dogs. Dogs and humans are similar in the spontaneous development of thyroid cancer and metastasis to lungs; however, thyroid cancer has a higher incidence of metastasis in dogs. This study developed a preclinical nude mouse model of canine thyroid cancer using a canine thyroid adenocarcinoma cell line (CTAC) and measured the expression of important invasion and metastasis genes in spontaneous canine thyroid carcinomas and CTAC cells. CTAC cells were examined by electron microscopy. Short tandem repeat analysis was performed for both the original neoplasm and CTAC cells. CTAC cells were transduced with luciferase and injected subcutaneously and into the tail vein. Tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Invasion and metastasis genes were characterized in 8 follicular thyroid carcinomas (FTCs), 4 C-cell thyroid carcinomas, 3 normal thyroids, and CTAC cells. CTAC cells grew well as xenografts in the subcutis, and they resembled the primary neoplasm. Metastasis to the kidney and lung occurred infrequently following subcutaneous and tail vein injection of CTAC cells. STR analysis confirmed that CTAC cells were derived from the original neoplasm and were of canine origin. Finally, 24 genes were differentially expressed in spontaneous canine thyroid carcinomas, CTAC, and normal thyroids. This study demonstrated the usefulness of a nude mouse model of experimental canine thyroid carcinoma and identified potential molecular targets of canine follicular and C-cell thyroid carcinoma.
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Ullrich, Martin, Josephine Liers, Mirko Peitzsch, Anja Feldmann, Ralf Bergmann, Ulrich Sommer, Susan Richter et al. "Strain-specific metastatic phenotypes in pheochromocytoma allograft mice". Endocrine-Related Cancer 25, n.º 12 (diciembre de 2018): 993–1004. http://dx.doi.org/10.1530/erc-18-0136.
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Somatostatin receptor-targeting endoradiotherapy offers potential for treating metastatic pheochromocytomas and paragangliomas, an approach likely to benefit from combination radiosensitization therapy. To provide reliable preclinical in vivo models of metastatic disease, this study characterized the metastatic spread of luciferase-expressing mouse pheochromocytoma (MPC) cells in mouse strains with different immunologic conditions. Bioluminescence imaging showed that, in contrast to subcutaneous non-metastatic engraftment of luciferase-expressing MPC cells in NMRI-nude mice, intravenous cell injection provided only suboptimal metastatic spread in both NMRI-nude mice and hairless SCID (SHO) mice. Treatment of NMRI-nude mice with anti-Asialo GM1 serum enhanced metastatic spread due to substantial depletion of natural killer (NK) cells. However, reproducible metastatic spread was only observed in NK cell-defective SCID/beige mice and in hairless immunocompetent SKH1 mice bearing disseminated or liver metastases, respectively. Liquid chromatography tandem mass spectrometry of urine samples showed that subcutaneous and metastasized tumor models exhibit comparable renal monoamine excretion profiles characterized by increasing urinary dopamine, 3-methoxytyramine, norepinephrine and normetanephrine. Metastases-related epinephrine and metanephrine were only detectable in SCID/beige mice. Positron emission tomography and immunohistochemistry revealed that all metastases maintained somatostatin receptor-specific radiotracer uptake and immunoreactivity, respectively. In conclusion, we demonstrate that intravenous injection of luciferase-expressing MPC cells into SCID/beige and SKH1 mice provides reproducible and clinically relevant spread of catecholamine-producing and somatostatin receptor-positive metastases. These standardized preclinical models allow for precise monitoring of disease progression and should facilitate further investigations on theranostic approaches against metastatic pheochromocytomas and paragangliomas.
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Yu, Lin, Yuxi Wang, Yuqin Yao, Wenting Li, Qinhuai Lai, Jun Li, Yongjun Zhou et al. "Eradication of Growth of HER2-Positive Ovarian Cancer With Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate in Mouse Xenograft Model". International Journal of Gynecologic Cancer 24, n.º 7 (septiembre de 2014): 1158–64. http://dx.doi.org/10.1097/igc.0000000000000179.
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ObjectiveOvarian cancer is 1 kind of a highly malignant gynecologic tumor, and current treatments have not achieved satisfactory effects. Human epidermal growth factor receptor 2 (HER2)–targeted therapies including trastuzumab and trastuzumab-DM1 (T-DM1) (antibody-cytotoxic drug conjugates) have been applied to treat HER2-overexpressing breast cancers in clinic. In the present study, we explored whether T-DM1 could effectively treat HER2-positive human ovarian carcinoma in vitro and in vivo.MethodsHER2 expressions of 6 ovarian cancer cell lines and 2 breast carcinoma cell lines were validated, and the binding capacity of T-DM1 to HER2-positive ovarian cancer SKOV3 cells were analyzed by flow cytometry. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effect of T-DM1.ResultsHigh HER2 expressions in SKOV3 cell lines were detected. The binding capacity of T-DM1 to HER2-positive SKOV3 cells was in a similar manner comparing with trastuzumab. In vitro, T-DM1 showed strong growth inhibitory on SKOV3 cells, with IC50 values of 0.15 nmol/L. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effects of T-DM1 in vivo. In subcutaneous xenografts model, T-DM1 (30 mg/kg and 10 mg/kg) indicated significant anticancer effects. It is noteworthy that tumors were completely eradicated in the T-DM1 (30 mg/kg) group, and no regrowth was observed in a long time after the termination of the treatment. In the peritoneal xenograft model, tumor nodules in 3 of 7 mice were hardly observed in the abdominal cavity of mice after intraperitoneal injection of T-DM1 (30 mg/kg). At the same time, tumor nodules from the other 4 mice weighed on the average of only 0.07 g versus 1.77 g in control group.ConclusionsOur data showed that T-DM1 possessed promising antitumor effects on HER2-overexpressing ovarian cancer in mouse model, which provided valuable references for the future clinical trials.
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Kute, T. E. y Y. Quadri. "Measurement of proliferation nuclear and membrane markers in tumor cells by flow cytometry." Journal of Histochemistry & Cytochemistry 39, n.º 8 (agosto de 1991): 1125–30. http://dx.doi.org/10.1177/39.8.1856460.
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Nuclear and membrane markers that have been related to proliferative activity were measured by flow cytometry. The markers studied were transferrin receptor (TR), Ki-67 antigen, and epidermal growth factor receptor (EGFR). Two-color analysis for DNA via propidium iodide binding and for antigen expression via either a direct or indirect immunofluorescence assay was performed on three different cell lines and a solid human tumor model. The three cell lines tested were MCF-7 (breast), K-562 (leukemia), and A431 (a squamous cell). The solid tumor was obtained by subcutaneous injection of A431 cells into an athymic nude mouse. Our results demonstrate that TR are cell-cycle specific and can be readily measured in the cell lines. Ki-67 antigen is also cell-cycle specific in the cell lines tested, but the mean channel specific fluorescence uptake varies in the cell types. Finally, the EGFR was observed only in the A431 cell line, with most cells equally expressing this receptor. A bimodal distribution of EGFR was observed in A431 cells obtained from a solid tumor grown in an athymic nude mouse system. This suggests that cell line analysis may not always represent what might be observed under in vivo conditions. There are advantages to flow cytometry measurements of these factors which might be useful in predicting how patients should be treated and possibly the prognosis of cancer patients.
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Longcor, Jarrod, Katherine Oliver y Irawati Kandela. "Efficacy of a single-dose injection of CLR 131 (1-131-CLR1404) in a Caki-2 athymic nude mouse model." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e14087-e14087. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14087.
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e14087 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a single dose intravenous injection in Caki-2 tumor bearing mice. Caki-2 cells are a human clear cell renal cell carcinoma (CCRCC). Methods: The Caki-2 cell line (human clear cell carcinoma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy’s 5a media supplemented with 10% fetal bovine serum. Female athymic nude mice (Hsd: Athymic Nude-Foxn1nu); 4-5 weeks of age, 16-18 g (Harlan, Indianapolis, IN) were injected subcutaneously with 1x106 viable cells (in 100 µL Dulbecco’s PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (100-250 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation. A single dose of ~110µCi of CLR 131 was given at Day 0 (N = 6 per group). A control dose of I-127-CLR1404 was given at ~110 µCi dose and was injected via tail vein on Day 0. Results: Tumor growth of the treatment group was significantly inhibited. The control group showed exponential growth after day 20 post-injection while the treatment group maintained the initial tumor volume up to day 75 post injection. By day 65, the control group increased 10.75-fold compared to the treatment group in average tumor volume. CLR 131 provides survival benefit for Caki-2 bearing mice. Kaplan Meier survival showed significant survival benefit with this model. Conclusions: The results of the study indicate that a single dose of CLR 131 on Caki-2 tumor bearing model showed a significant inhibition of tumor growth as well as significant survival benefit.
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Wang, Mengling, Xueyi Zeng, Shengyou Li, Zekun Sun, Jia Yu, Chao Chen, Xiangchun Shen, Weidong Pan y Heng Luo. "A Novel Tanshinone Analog Exerts Anti-Cancer Effects in Prostate Cancer by Inducing Cell Apoptosis, Arresting Cell Cycle at G2 Phase and Blocking Metastatic Ability". International Journal of Molecular Sciences 20, n.º 18 (10 de septiembre de 2019): 4459. http://dx.doi.org/10.3390/ijms20184459.
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Prostate cancer (PCa), an epithelial malignant tumor, is the second common cause of cancer death among males in western countries. Thus, the development of new strategies is urgently needed. Tanshinones isolated from Salvia miltiorrhiza and its synthetic analogs show various biological activities including anticancer effects. Among them, the tanshinone analog 2-((Glycine methyl ester)methyl)-naphtho (TC7) is the most effective, with better selectivity and lower toxicity. Therefore, in this work, the effect of TC7 against PCa was investigated through assessing the molecular mechanisms regulating the growth, metastasis, and invasion of PCa cells. Human PCa cells, PC3 and LNCAP, were used to evaluate TC7 mechanisms of action in vitro, while male BALB/c nude mice were used for in vivo experiments by subjecting each mouse to a subcutaneous injection of PC3 cells into the right flank to evaluate TC7 effects on tumor volume. Our in vitro results showed that TC7 inhibited cell proliferation by arresting the cell cycle at G2/M through the regulation of cyclin b1, p53, GADD45A, PLK1, and CDC2/cyclin b1. In addition, TC7 induced cell apoptosis by regulating apoptosis-associated genes such as p53, ERK1, BAX, p38, BCL-2, caspase-8, cleaved-caspase-8, PARP1, and the phosphorylation level of ERK1 and p38. Furthermore, it decreased DNA synthesis and inhibited the migration and invasion ability by regulating VEGF-1 and MMP-9 protein expression. Our in vivo evidence supports the conclusion that TC7 could be considered as a potential promising chemotherapeutic candidate in the treatment of PCa.
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Sosnovtceva, Anastasiia O., S. Sh Karshieva, G. B. Smirnova, Yu A. Borisova, O. V. Lebedinskaya, I. Zh Shubina, H. M. Treshalina, P. M. Chumakov y V. P. Chekhonin. "SENSITIVITY OF THE TRANSPLANTED HUMAN NEUROBLASTOMA TO ONCOLYTIC СOXSACKIE A7 VIRUS". Russian Journal of Oncology 22, n.º 3 (15 de junio de 2017): 158–63. http://dx.doi.org/10.18821/1028-9984-2017-22-2-158-163.
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Oncolytic viral therapy is a promising approach to targeted therapy of malignant tumors. In this article we consider the therapeutic potential of a non-pathogenic Coxsackie A7 virus (CA7V) with neurotropic properties on a model of human neuroblastoma. Purpose to study in vitro/in vivo sensitivity of human neuroblastoma HNB (from cell line JMR-32) to Coxsackie virus A7 (CA7V). Objectives: еvaluation of cytolytic activity in vitro on NB cells verified by cytomorphology and assessment of dynamics of the growth of subcutaneous neuroblastoma xenografts in Balb/c nude male mice exposed to CA7V multiple i.v. injections. Material and methods. CA7V was produced in the cells of line-producer С-33А. Cell culture and the strain of transplanted NB (JMR-32) were obtained from the Collection of N.N. Blokhin Russian Cancer Research Center. Cytomorphologic verification of neuroblastoma and CA7V cytolytic activity were executed with the use of standard cultural methods, TCID50 and IC50 criteria. Experiments «in vivo» were performed on immunodeficient Balb/c nude male mice bred and reared in the N.N. Blokhin Russian Cancer Research Center. The experiments were made at day 6 when neuroblastoma subcutaneous xenografts developed to the Vmean = 79-82 mm3 by day 6. The treatment with CA7V at the i.v. single dose of 1×108 cells per mouse was performed 3 times with 72-hours intervals; evaluation of the efficacy was made according to standard criterion Т/С ≤ 42%; and control of the tumor growth rate (Vt/V0) in the dynamics. Statistical assessment was made with the software Excel for Windows 2007 with the use of T-test under p ≤ 0.05. Results. Cytolytic effect of CA7V on neuroblastoma cells was registered similar to basic parameters of the original line-producer С-33А: TCID50 = 0.99×10-4 pfu/cell, and IC50 = 1.11×10-4 pfu/cell; 48 and 72 hours after virus reproduction in NB cells the rate was 2.0 and 1.5-fold higher than in the line-producer cells. СA7V inhibiting effect on the growth of large subcutaneous neuroblstoma xenografts is registered after the first i.v. injection at the minimal level of T/C = 67% (criterion ≤ 42%) with the 1.5-fold decrease of the tumor growth rate and cancellation of early mice death by day 22 vs day 15 in the control group of untreated mice (n = 8). Conclusion. The obtained results allow to consider human neuroblastoma (JMR-32) to possess the low sensitivity to oncolytic effect of in vitro/in vivo. In order to obtain significant effect in vivo the treatment should be started in mice with 2-fold smaller tumors and a higher initial dose of the oncolytic agent.
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Protasova, Tatyana, Anna Goncharova, Ekaterina Lukbanova, Vyatcheslav Volovik, Mariya Mindar, Dariya Khodakova, Anastasia Volkova et al. "Development of method for creating tumor xenograft model with porous metal scaffold". Problems in oncology 67, n.º 1 (4 de marzo de 2021): 127–33. http://dx.doi.org/10.37469/0507-3758-2021-67-1-127-133.
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Aim of the study – the development of a method for obtaining a tumor xenograft model by a subcutaneous transplantation of a porous metal scaffold populated with cultured human lung carcinoma cells. Material and methods. The study included 14 athymic male Balb c/nude mice aged 8-90 weeks, weighing 20-24 g. All animals received injections with cultured human A549 lung carcinoma cells subcutaneously into the right anterolateral area of the back. In animals of the main group (gr.1, n=4), scaffolds with a pore diameter of 0.5 mm made of titanium-aluminum-vanadium alloy using an industrial 3D printer served as carriers of tumor cells. Scaffolds were seeded with 3 million A549 culture cells, and were implanted into the recipient animals after the 7-day incubation. Results were compared with the results of the tumor culture transplantation with Matrigel (100 mcL) in two groups of animals with varying cell suspension dosages: the maximum vaccination dose for in vivo (10×106 cells per mouse, gr.2, n=5) and half the maximum dose (5×106 respectively, gr.3, n=5). Then, the dynamics of tumor growth in the groups of experimental mice was monitored for 55 days: xenograft volumes were calculated using the Shrek’s formula for an ellipsoid. At the end of the experiment, the animals were euthanized by cervical dislocation. Results. Monitoring of the dynamics of xenograft volumes demonstrated the maximal values in mice with implanted scaffolds. The slowest xenograft growth was registered in animals with the maximum vaccination dose of tumor cells with Matrigel. Histological study showed that tumor material obtained from all animals corresponded to A549 lung carcinoma. Conclusions. Porous metal scaffolds, previously incubated with A549 culture cells and implanted subcutaneously in athymic Balb c/nude mice, allows obtaining rapidly growing xenografts with histologically confirmed correspondence to the original tumor.
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Hu, Liang, Merlin Lee, Wendy Campbell, Roman Perez-Soler y Simon Karpatkin. "Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis". Blood 104, n.º 9 (1 de noviembre de 2004): 2746–51. http://dx.doi.org/10.1182/blood-2004-03-1047.
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Abstract Tumor/host-generated thrombin (endogenous thrombin) was investigated with tumor growth and metastasis experiments in mice by the use of hirudin, a highly potent specific inhibitor of thrombin. Pretreatment with hirudin inhibited tumor implantation in nude or syngeneic mice, following subcutaneous injection of 2 human and 2 murine tumors. Hirudin induced a considerable lag period in the appearance of tumor growth, compared with phosphate-buffered saline (PBS) treatment, but had no effect on established tumor nodule growth in vivo or on tumor growth in vitro. Hirudin treatment induced central necrosis of the tumor nodule compared with no effect with PBS treatment. Greater protection was noted with longer duration of treatment. Tumor seeding into blood was examined with green fluorescent protein (GFP)-labeled tumor cells. Hirudin inhibited seeding into the blood as well as systemic organs which varied from complete protection to 15- to 32-fold in the blood and 17- to 395-fold in the lung. Hirudin inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs. Mouse survival in animals injected subcutaneously with highly aggressive 4T1 cells revealed 5 of 5 deaths of PBS-treated animals on day 40 compared with no deaths with hirudin treatment, with prolongation of survival with hirudin treatment of 16 days to more than 31 days. Thus, endogenous thrombin contributes to tumor implantation, seeding, and spontaneous metastasis. A potent antithrombin agent should be of clinical benefit to patients with cancer. (Blood. 2004;104:2746-2751)
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Oliver, Katherine, Jarrod Longcor y Irawati Kandela. "Efficacy of repeated injections of CLR 131 (I-131-CLR1404) in a MES SA/Dx5 athymic nude mouse model." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e14091-e14091. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14091.
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e14091 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Uterine sarcoma (MES SA/Dx5) cells express high levels of P-gp and are known to be a doxorubicin resistant cell line. The cells exhibit a marked cross resistance to several chemotherapy drugs including vinblastine, Taxol®, vincristine, etc. This study evaluates the effect of repeated injections of CLR 131 in MES SA/Dx5 tumor bearing mice and evaluate the ability of CLR 131 to overcome resistance caused by over-expression of the P-gp Multi Drug Resistance (MDR) ‘pump’. Methods: The MES SA/Dx5 cell line (human uterine sarcoma) was purchased from American Type Culture Collection (Rockville, MD) and maintained in McCoy’s 5a media supplemented with 10% fetal bovine serum. Female athymic nude mice (Crl: NU-Foxn1nu); approximately 4-5 weeks of age and between 16-18 g (Charles River, Portage, MI) were injected subcutaneously with 2x106 viable cells (in ~100 µL Dulbecco’s PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (approximately 50-150 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation. Doses of ~130 µCi and ~145 µCi of CLR 131were given at Day 0 and Day 7 (N = 6 in treatment group, N = 5 in control group). A single control dose of ~130 µCi of I-127-CLR1404 was given via tail vein injection on Day 0. Results: Tumor growth of the treatment group was significantly inhibited. The control group showed exponential growth throughout the study, increasing in volume by an average 21 fold from baseline to day 22 (all control mice died day 23). This compared with a 6 fold increase from baseline in the treatment group. Conclusions: The results of the study indicated that multiple injections of CLR 131 on human uterine sarcoma (MES SA/Dx5) tumor bearing model showed a significant inhibition of tumor growth as well as significant survival benefit. The implication is that in this clinically predictive in vivo model CLR 131 is not susceptible to the MDR “pump” and thus CLR 131 might show clinical efficacy in patients with MDR cancer due to P-gp overexpression.
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Lu, John, Christopher M. Haqq y HQ Han. "Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer." Journal of Clinical Oncology 31, n.º 15_suppl (20 de mayo de 2013): 2541. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2541.
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2541 Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC50 < 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p<0.0001) tumor growth reduction, versus the vehicle-treated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p<0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p<0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.
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Yi, B. R. y K. C. Choi. "306 ANTITUMOR EFFECT OF ENDOMETRIAL CANCER MASS WAS INDUCED BY THERAPEUTIC STEM CELLS FUSED CYTOSINE DEAMINASE AND INTERFERON-BETA IN A NUDE MOUSE MODEL". Reproduction, Fertility and Development 25, n.º 1 (2013): 300. http://dx.doi.org/10.1071/rdv25n1ab306.
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Endometrial cancer has been reported as the most common malignancy, accounting for ~50% of the uterine tumour cases in the Western world. An exact mechanism underlying the development of this type of cancer is unclear. In our previous study, we confirmed the therapeutic efficacy of stem cells expressing bacterial cytosine deaminase (CD) and/or human interferon-β (IFN-b) gene against endometrial Ishikawa cells in an in vitro model. The CD gene can convert a nontoxic prodrug, 5-fluorocytosine (5-FC), to the toxic agent, 5-fluorouracil (5-FU), and IFN-b is a powerful cytokine that has antiviral effects. In this study, we generated xenografted mice baring Ishikawa endometrial cancer cells and confirmed the therapeutic efficacy of these stem cells. For generation of an animal model of endometrial cancer, Ishikawa cells (2 × 106 cells/mouse) were implanted subcutaneously in severe combined immunodeficiency (SCID) mice. Next, the stem cells stained CM-DiI as red fluorescence were injected into nearby tumour mass and, 1 day after stem cell injection, 5-FC (500 mg kg–1 per day) was adminstered through an intraperitoneal injection per day for 14 days. Two days after final injection of the prodrug, we killed these mice and extracted the endometrial tumour mass. Tumour volumes reached 1400 and 450 mm3 in control mice and mice injected with stem cells, respectively, and fused gene expression of CD and/or IFN-b significantly inhibited the growth of endometrial cancer mass in the presence of 5-FC (~50 to 60%). In addition, we confirmed the migratory effect of the stem cells using a fluorescent analysis; red-stained HB1.F3.CD and HB1.F3.CD.IFN-b cells were found in the extracted endometrial cancer mass. A histological analysis of tumour mass showed that the aggressive property of endometrial cancer was inhibited in the presence of a prodrug in mice treated with therapeutic stem cells. Taken together, these results provide evidence for the usefulness of therapeutic stem cell-based gene therapy through a targeted delivery of therapeutic gene products to endometrial cancer sites. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea government (no. 2010-0003093).
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Lin, Yu-Chao, Jui-Hsin Su, Shih-Chao Lin, Chia-Che Chang, Te-Chun Hsia, Yu-Tang Tung y Chi-Chien Lin. "A Soft Coral-Derived Compound, 11-Dehydrosinulariolide, Induces G2/M Cell Cycle Arrest and Apoptosis in Small Cell Lung Cancer". Marine Drugs 16, n.º 12 (30 de noviembre de 2018): 479. http://dx.doi.org/10.3390/md16120479.
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11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral Sinularia flexibilis, has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was applied to evaluate cell cycle distribution and apoptosis. The expression of proteins related to the cell cycle and apoptosis was analyzed by Western blot analysis. Additionally, an in vivo study was performed to determine the anti-SCLC effect on an H1688 subcutaneous tumor in a BALB/c nude mouse model. 11-Dehydrosinulariolide inhibited cell growth, triggered G2/M arrest and induced H1688 cell apoptosis in a dose- and time-dependent manner. Additionally, 11-dehydrosinulariolide caused the accumulation of p53 and Bax, accompanied by the activation of DNA damage-inducing kinases, including ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2). Moreover, 11-dehydrosinulariolide increased the activity of caspase-3 and -7, suggesting that caspases are involved in 11-dehydrosinulariolide-induced apoptosis. 11-Dehydrosinulariolide also increased the level of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibited the expression of phosphorylated Akt. In the in vivo study, the intraperitoneal injection of 11-dehydrosinulariolide at a dosage of 10 mg/kg significantly inhibited tumor growth compared with the control treatment. Together, the data indicate that 11-dehydrosinulariolide induces G (2)/M cell cycle arrest and apoptosis through various cellular processes, including the upregulation of p53 and Bax, activation of ATM and Chk2, activation of caspase-3 and -7, and accumulation of PTEN, leading to inhibition of the Akt pathway. These findings suggest that 11-dehydrosinulariolide might serve as a promising chemotherapy drug in the treatment of SCLC.
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Chan, A. D., G. A. Luiken, M. M. Quigley, M. Xu y R. M. Hoffman. "Induced fluorescence of breast cancer in the mouse model: A simple technology to improve visualization of malignant tissue during breast cancer surgery". Journal of Clinical Oncology 24, n.º 18_suppl (20 de junio de 2006): 10557. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10557.
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10557 Background: Accurate identification of all malignant tissue at the time of lumpectomy or mastectomy can at times be challenging. When positive margins are discovered, significant additional time and effort may be required by the surgeon to complete the initial procedure. Inducing the cancer cells to be fluorescent offers the potential to improve the surgeon’s ability to rapidly and accurately identify and excise the malignant tissue at the time of surgery. We have previously demonstrated the feasibility of inducing tumor fluorescence with fluorophore-tagged anti-tumor antigen antibodies using a human colon cancer cell line. We present here our recent results using a human breast cancer cell line in the nude mouse. Methods: A human breast cancer cell line, MDA-MB-468 known to express CA 15–3 was used. Breast cancer cells were subcutaneously implanted in 14 nude mice. Three to five weeks after injection, tumor nodules were easily visible and palpable. Using the tail vein method, mice were injected with fluorophore-tagged anti-CA 15–3 and were examined using a small animal imaging system with a 470 nm light source. Mice were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band-pass filter and were observed through filtered goggles. Results: Tumor nodules could be seen to fluoresce through the skin when illuminated with a 470 nm light source. When tumor nodules were exposed and examined with white light, the nodules could be seen but when illuminated with the 470 nm light source, tumor fluorescence allowed clear identification of nearby small tumor nodules and clear identification of tumor margins easily distinguishable from the normal tissue. Conclusions: For this technology to work, tumor antigens must be known and antibodies to these antigens available. It is easy to perform, requires no complex equipment or operator expertise and could be easily adapted to surgical oncology in any hospital setting. It has the potential to improve surgical accuracy in women undergoing initial lumpectomy or mastectomy as well as axillary lymph node dissection or sentinel node biopsy. In addition it could aid in the surgery of patients undergoing resection of isolated recurrent hepatic or pulmonary metastases. No significant financial relationships to disclose.
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Luiken, G. A., M. Xu, M. M. Quigley, R. M. Hoffman y A. D. Chan. "Fluorescent antibody tagging of colon cancer in the nude mouse; a model for improved surgical accuracy in the oncologic patient". Journal of Clinical Oncology 24, n.º 18_suppl (20 de junio de 2006): 13501. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13501.
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13501 Background: Induced fluorescence of malignant tumors has the potential to improve the surgeon’s ability to accurately identify and excise all malignant tissue. Tumors can be made fluorescent using fluorophore-tagged anti-tumor antigen antiboies. We present here our results using a human colon cancer cell line in the nude mouse model. Methods: HCT 116 colon cancer cells were subcutaneously or orthotopically implanted in 16 nude mice (12 study mice and 4 control mice). Two to 8 weeks after injection, tumor nodules were easily detectable. Using the tail vein method, all mice were injected with fluorophore-tagged anti-CEA or fluorophore-tagged IgG. Mice were examined using a small animal imaging system with a 470 nm light source and appropriate filters. They were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band pass filter for illumination and were observed through filtered goggles. Results: All tumor nodules in the study mice demonstrated green fluorescence when visualized through the skin. On dissection and exposure of the tumor nodules, this fluorescence was intense and clearly distinguishable from the surrounding normal tissue using either the imaging system or the blue LED. Very small (<0.5mm) metastatic nodules were easily identified. Bright tumor fluorescence remained visible up to 5 days after injection. Control mice injected with fluorophore-tagged IgG and examined in a similar manner revealed no tumor fluorescence. Minimal non-specific dull fluorescence was occasionally observed in gut mucosa and ovarian tissue but was easily distinguished from the bright tumor fluorescence. Conclusions: When tumor surface antigens are known and antibodies to those antigens are available, this technology is simple, easy to perform, requires no technically complex equipment or operator expertise and could be readily adapted for cancer surgery in the academic or community hospital setting. Major indications for this technology would be in those patients where tumor resection offers an excellent chance for cure or significantly improves survival. The implications for increased accuracy of procedures such as resection of primary colorectal cancer or resection of solitary hepatic or pulmonary metastases are clear. No significant financial relationships to disclose.
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Johnson, T. E., G. A. Luiken, M. M. Quigley, M. Xu y R. M. Hoffman. "Induced fluorescence of medullary carcinoma of the thyroid: A technology with potential to improve visualization of malignant tissue at the time of surgical resection". Journal of Clinical Oncology 24, n.º 18_suppl (20 de junio de 2006): 15503. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.15503.
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15503 Background: Surgery for medullary carcinoma of the thyroid can at times be technically challenging to the surgeon. Inducing the cancer cells to be fluorescent would have the potential to improve the surgeon’s ability to quickly and accurately identify and excise all of the malignant tissue. We have previously demonstrated the feasibility of induced tumor fluorescence with fluorophor-tagged anti-tumor antigen antibodies using human colon and breast cancer cell lines. We present here our results using a human medullary carcinoma of the thyroid cell line in the nude mouse model. Methods: A human medullary carcinoma of the thyroid cell line that was demonstrated to express CA 15–3 was used. Thyroid carcinoma cells were subcutaneously implanted in 4 nude mice (3 study mice and 1 control mice). Three weeks after injection, tumor nodules were easily detectable. Using the tail vein method, 3 study mice were injected with fluorophore-tagged anti-CA 15–3 and 1 control mouse with fluorophore-tagged IgG. Mice were examined using a small animal imaging system with a 470 nm light source and appropriate filters. They were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band pass filter for illumination and were observed through filtered goggles. Results: Fluorescence of tumor nodules in the study mice could be seen through the skin. On dissection and exposure of the tumor nodules, this fluorescence was intense and clearly distinguishable from the surrounding normal tissue using either the imaging system or the blue LED. The control mouse injected with fluorophore-tagged IgG and examined in a similar manner revealed no tumor fluorescence. Conclusions: When tumor antigens are known, fluorophore-tagged antibody induced fluorescence is simple, easy to perform, requires no technically complex equipment or operator expertise and could be adapted to thyroid cancer surgery in the academic or community hospital setting. This technology would be indicated in those patients undergoing initial resection of medullary carcinoma of the thyroid as well as in those patients undergoing resection of recurrent disease where accurate identification of tumor tissue may be more difficult and time consuming. No significant financial relationships to disclose.
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Yoshino, Takayuki, Jun Miyazaki, Takahiro Kojima, Shuya Kandori, Hideyuki Akaza, Ikuya Yano y Hiroyuki Nishiyama. "Antitumor effect of cationic liposome incorporating keto-mycolic acid from Mycobacterium bovis bacillus Calmette-Guérin in mouse model." Journal of Clinical Oncology 36, n.º 6_suppl (20 de febrero de 2018): 461. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.461.
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461 Background: Intravesical instillation of live bacillus Calmette-Guérin (BCG) is an established immunotherapy for non-muscle invasive bladder cancer. However, development of non-infectious agents has been expected, because there are several problems due to instillation of live bacteria. BCG cell wall skeleton is known to stimulate host immune system, but the mechanism is still unknown. Mycolic acid (MA), which consist of three subclasses (α, keto, methoxy), is the most abundant lipid component of BCG cell wall and is expected to be one of essential active components. Objective: In order to identify active component from BCG cell wall and develop non-infectious BCG-derived immunotherapy, anti-tumor activities of cationic liposomes incorporating each subclass of MA were assessed using mouse syngeneic graft model. Methods: Heat killed packed cells of M. bovis BCG Tokyo 172 were fully hydrolyzed and MA was obtained. MA was separated to three subclasses by thin layer chromatography. Cationic and hydrophilic liposomes incorporating each subclass of MA were prepared. C57BL/6 mice were subcutaneously inoculated with a mixture of MB49 cells and PBS or liposome with/without MA followed by additional injection of PBS or liposome. Tumor growth was monitored. Infiltration of CD4/8 lymphocytes was examined by immunostaining. Results: Cationic liposomes were internalized into cytoplasm of MB49 cells, a mouse bladder cancer cell line. Cell proliferation was not affected by liposome incorporating MA. Tumor growth was significantly suppressed in mice treated with keto MA-liposome (vs PBS, p = 0.007), but not in mice treated withα-or methoxy-MA liposomes. Number of infiltrating CD8 lymphocytes was higher in tumor treated with keto MA-liposome than control. Antitumor effect of keto MA-liposome disappeared in nude mouse, while the effect existed in beige mouse with NK activity deficiency (vs PBS, p = 0.045). Conclusions: Keto MA-liposome showed the strongest antitumor effects in mouse model among three subclasses. T cell immunity may contribute to those effects.
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Zhang, Tiantian, Dennis H. Kordish, Yogesh R. Suryawanshi, Rob R. Eversole, Steven Kohler, Charles D. Mackenzie y Karim Essani. "Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells". Current Cancer Drug Targets 18, n.º 6 (11 de junio de 2018): 577–91. http://dx.doi.org/10.2174/1568009617666170630143931.
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Background: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system. Objective: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2. Methods: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3. Results: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R. Conclusion: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy.
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Holder, Sheldon L. y Jeffrey Small. "An evaluation of abemaciclib activity in combination with sunitinib in renal cell carcinoma." Journal of Clinical Oncology 35, n.º 6_suppl (20 de febrero de 2017): 452. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.452.
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452 Background: The majority of therapeutic agents used in renal cell carcinoma (RCC) target the vascular endothelial growth factor and mammalian target of rapamycin pathway. Exceptions include the immunotherapy agents interleukin-2 and nivolumab. To change the natural history of RCC and improve upon current treatment regimens we believe new therapeutic targets are necessary. CDK4/6 and PIM1 kinase have both been identified as possible therapeutic targets in RCC. Abemaciclib is a potent inhibitor of both CDK4/6 and PIM1 kinases. We have demonstrated that abemaciclib causes increased apoptosis and decreased cellular viability in RCC cell lines and tumor responses in mice (submitted). Here we report the results of an additional pre-clinical study of the effects of abemaciclib alone and in combination with sunitinib. Methods: Tumors were established in nude mice by subcutaneous flank injection of 786-O cells. Tumors were allowed to establish and grow to about 1 cm. Mice were treated by oral gavage with vehicle, sunitinib, abemaciclib, or combination. Tumors were measured with calipers to determine response. Mice that received sunitinib were subsequently treated with combination therapy and response determined by caliper measurement. At the conclusion of the course of treatment mice were euthanized and the tumors removed, weighed, fixed, and embedded in paraffin. Results: Mice treated with vehicle had continued tumor growth during the course of therapy. Mice treated with sunitinib showed mostly disease stabilization, paralleling the response seen in clinic. Mice in the abemaciclib cohort showed gradual decline in tumor size over the course of treatment. Mice in the combination therapy cohort exhibited a rapid reduction in tumor size with sustained response. Interestingly mice in the sunitinib cohort experiencing stable disease or growing tumor had rapid decrease in tumor size with the initiation of combination therapy. Conclusions: Abemaciclib is active in a mouse model of RCC. The combination of abemaciclib/sunitinib causes rapid reduction in tumor size in treatment naïve and sunitinib pre-treated mice. These data support the use of combination abemaciclib/sunitinib therapy in a human clinical trial.
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Zhao, Yunqi, Ran Chen, Yun Wang y Yixin Yang. "α-Pinene Inhibits Human Prostate Cancer Growth in a Mouse Xenograft Model". Chemotherapy 63, n.º 1 (26 de octubre de 2017): 1–7. http://dx.doi.org/10.1159/000479863.
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Background: α-Pinene is one of the most widely found terpenoids in nature. Substantial evidence shows that α-pinene has cancer prevention properties. In this study, the PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Methods: Cytotoxicity was measured with the MTT assay, and apoptosis and cell cycle analyses were conducted using flow cytometry in vitro. The PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Results: We found that treatment with α-pinene significantly inhibited human prostate cancer cell growth and induced apoptosis and cell cycle arrest in the cell line-based model. Furthermore, tumor progression was inhibited more in mice treated with α-pinene than in control mice. We detected less Ki67 and proliferation cell nuclear antigen in paraffin sections from xenograft tumor specimens taken from α-pinene-treated mice than in those from the control group. Meanwhile, α-pinene treatment induced apoptosis in xenograft tumors as determined by the TUNEL assay. Conclusions: These data strongly suggest that α-pinene inhibits prostate cancer growth in a xenograft model and may be an effective therapeutic agent for prostate cancer treatment.
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Zhang, Ying, Li Luo, Xueling Zheng y Tinghe Yu. "An Advanced Orthotopic Ovarian Cancer Model in Mice for Therapeutic Trials". BioMed Research International 2016 (2016): 1–4. http://dx.doi.org/10.1155/2016/2585787.
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A nude mouse received subcutaneous injection of human ovarian cancer cells HO-8910PM to form a tumor, and then the tumor fragment was surgically transplanted to the ovary of a recipient mouse to establish an orthotopic cancer model. Tumors occurred in 100% of animals. A mouse displayed an ovarian mass, ascites, intraperitoneal spread, and lung metastasis at natural death. The mean survival time was34.1±17.2days, with median survival time of 28.5 days. The findings indicated that the present mouse model can reflect the biological behavior of advanced human ovarian cancers. This in vivo model can be used to explore therapeutic means against chemoresistance and metastasis, and an effective treatment would prolong the survival time.
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Zhu, Yin, Yi Hu, Ming Cheng, Chun-Yan Zeng, Zhen Yang, Xiao-Dong Zhou, Jiang Chen y Nong-Hua Lu. "Establishment and Characterization of a Nude Mouse Model of Subcutaneously Implanted Tumors and Abdominal Metastasis in Gastric Cancer". Gastroenterology Research and Practice 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/6856107.
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A mouse gastric cancer model is an important tool for studying the mechanisms of gastric cancer. To establish subcutaneously implanted tumors, MKN-45 cell suspensions and tumor tissues were implanted into the middle of the right armpit of nude mice. To generate an abdominal metastasis model, MKN-45 cell suspensions and tumor tissue homogenates were implanted into the middle of the lower abdomen. We measured the weights of the nude mice and the longest dimension, shortest dimension, thickness, and volume of the tumor. We also analyzed the rate of tumor formation, the time required for tumor formation, and the number and size of abdominal tumors in the mice. The rates of formation of the subcutaneously implanted tumors were 100%, 0%, and 100% in the nude mice inoculated with 2 × 107cells/mL or 1 × 107cells/mL of the MKN-45 cell suspension or the tumor tissue homogenate (2 × 107cells/mL), respectively. The rates of metastatic abdominal tumor formation were 100%, 50%, and 75% in mice inoculated with 5 × 107cells/mL or 1 × 107cells/mL of the tumor tissue homogenate or the MKN-45 cell suspension (5 × 107cells/mL), respectively. We derived tumor tissues and tumor tissue homogenates from nude mice prior to establishing the subcutaneous model of implanted tumors and the abdominal metastasis model of gastric cancer, respectively.
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Zhang, Wen-Ying, Zhen-Dong Jin, Feng Liu, Hai-Hua Yuan y Bin Jiang. "Antitumor Activity of Intratumoral Ethanol Injection in an Orthotopic Pancreatic Cancer Cell Mouse Xenograft Model". Gastroenterology Research and Practice 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/7149565.
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Purpose. Pancreatic cancer is a lethal disease and usually is diagnosed at advanced stages of disease. This study assessed the effects of intratumoral ethanol injection using an endoscopic ultrasound (EUS) probe on the control of pancreatic cancer in a mouse orthotopic xenograft model. Materials and Methods. The subcutaneous and orthotopic human pancreatic cancer cell mouse xenograft models were established. Different concentrations of ethanol (0–95%) were injected into subcutaneous xenograft tumors. In the orthotopic tumor model, ethanol was injected into the tumor lesions under the guidance of a high-frequency EUS probe. Tumor volume, relative tumor volume (RTV), and histopathology were evaluated. The serum amylase level was analyzed at baseline and 24 h after treatment in the orthotopic tumor model. Results. Injection of 40–95% ethanol induced tumor necrosis in the subcutaneous tumor model, while there was no statistical difference between the RTVs of the two groups (P=0.81). In the orthotopic tumor model, the RTV of the 80% ethanol treatment group was less than that of the saline injection group (P<0.01); and histologically, there was a large area of necrosis observed in the 80% ethanol group. The serum amylase level was slightly elevated at 24 h after injection and returned to the baseline level at 7 days. Conclusion. Injection of 80% ethanol into xenograft tumor lesions of orthotopic pancreatic cancer resulted in tumor necrosis, and the procedure was safe and effective. Future studies will further confirm its antitumor activity as well as assess its safety and feasibility.
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Zhang, Lei, Chengyu Wu, Yong Zhang, Xiaoen Wang, Jose Reynoso, Robert M. Hoffman y Ming Zhao. "Imageable orthothopic metastatic mouse models for the identification of the antitumor and antimetastatic efficacy of traditional Chinese medicine (TCM)." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): e14700-e14700. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14700.
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e14700 Background: Traditional Chinese Medicine (TCM) is still poorly understood with regard to the types of cancer it is effective against, as well as its mechanism of action. Modernization of TCM evaluation is necessary in order for TCM to be effectively developed. We report here on the use of patient-like orthotopic nude-mouse models of metastatic cancer to obtain proof-of-concept that TCM combinations can have anti-tumor and anti-metastatic activity. Methods: In the present study, human and mouse lung cancer and pancreatic cancer cell lines (H460, Lewis lung carcinoma [LLC] and MIA-PaCa-2, respectively), labeled with red fluorescent protein (RFP) or green fluorescent protein (GFP) were used. The cells were initially implanted subcutaneously or injected in the tail vein in nude mice. Subcutaneous tumors were harvested to obtain tissue fragments which were implanted orthotopically in nude mice. These models were used to evaluate the anti-tumor and anti-metastatic efficacy of the TCM termed Fufang LQ (LQ), which contains a mixture of Chinese herbs. Results: LQ (gavage, 600 mg/kg/day) significantly inhibited pancreatic and lung cancer tumor growth as measured by imaging, tumor and weight in both subcutaneous and orthotopic models. LQ was significantly efficacious against primary and metastatic cancer in the above models without weight loss in contrast to drugs such as doxorubicin and cisplatin, which caused significant weight loss. Survival of tumor-bearing mice was also prolonged by LQ treatment. Conclusions: The results of the present study indicate that TCM can have non-toxic efficacy, in contrast to standard chemotherapy drugys, against metastatic pancreatic and lung cancer in clinically-relevant orthotopic mouse models of cancer, an important step toward the clinical development of TCM.
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Ip, Joseph Chok Yan, Josephine Mun Yee Ko, Valen Zhuoyou Yu, Kwok Wah Chan, Alfred K. Lam, Simon Law, Daniel King Hung Tong y Maria Li Lung. "A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma". BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/910715.
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Increasing evidence indicates tumor-stromal interactions play a crucial role in cancer. Anin vivoesophageal squamous cell carcinoma (ESCC) orthotopic animal model was developed with bioluminescence imaging established with a real-time monitoring platform for functional and signaling investigation of tumor-stromal interactions. The model was produced by injection of luciferase-labelled ESCC cells into the intraesophageal wall of nude mice. Histological examination indicates this orthotopic model is highly reproducible with 100% tumorigenesis among the four ESCC cell lines tested. This new model recapitulates many clinical and pathological properties of human ESCC, including esophageal luminal stricture by squamous cell carcinoma with nodular tumor growth, adventitia invasion, lymphovascular invasion, and perineural infiltration. It was tested using an AKT shRNA knockdown of ESCC cell lines and thein vivotumor suppressive effects of AKT knockdown were observed. In conclusion, this ESCC orthotopic mouse model allows investigation of gene functions of cancer cells in a more natural tumor microenvironment and has advantages over previous established models. It provides a versatile platform with potential application for metastasis and therapeutic regimen testing.
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Tinkey, Peggy T., Mira Milas y Raphael E. Pollock. "Reliable Establishment of Human Sarcoma Xenografts in the Nude Rat". Sarcoma 3, n.º 2 (1999): 129–33. http://dx.doi.org/10.1080/13577149977767.
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Purpose.The ability to establish consistent human tumor xenografts in experimental animals is a crucial part of preclinical investigations.The goal of this study was to develop a method of establishing a human tumor xenograft in the leg of a nude rat for evaluation of new surgical and molecular methods of treatments of human extremity sarcoma.Methods and results.Initial attempts to produce sarcoma nodules by subcutaneous injection of a human leiomyosarcoma tumor cell suspension (SKLMS-1) resulted in tumor nodule formation in only four of 10 sites (40%).The xenograft method was modified to include younger nude rats of a different source and substrain (HSD:rnu/rnu, 5–9 weeks old), treated with 500 cGy whole-body irradiation, and the transplantation of tumor cells or small tumor fragments which had been embedded in Matrigel.These changes improved the tumor take rate per site to 52/52 (100%).Tumor nodules demonstrated rapid and progressive growth and histological features consistent with the original human sarcoma.Discussion.Successful human leiomyosarcoma establishment in these nude rats permits the investigation of sarcoma biology and treatment with surgical procedures for which a mouse model would be inadequate. In this study we identified modifications in technique which enhanced the xenografting of a leiomyosarcoma cell line in nude rats; these techniques may increase tumor take rates for other tumor types as well.
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Nonaka, Motohiro, Misa Suzuki-Anekoji, Jun Nakayama, Hideaki Mabashi-Asazuma, Donald L. Jarvis, Jiunn-Chern Yeh, Kazuhiko Yamasaki et al. "Overcoming the blood–brain barrier by Annexin A1-binding peptide to target brain tumours". British Journal of Cancer 123, n.º 11 (14 de septiembre de 2020): 1633–43. http://dx.doi.org/10.1038/s41416-020-01066-2.
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Abstract Background Annexin A1 is expressed specifically on the tumour vasculature surface. Intravenously injected IF7 targets tumour vasculature via annexin A1. We tested the hypothesis that IF7 overcomes the blood–brain barrier and that the intravenously injected IF7C(RR)-SN38 eradicates brain tumours in the mouse. Methods (1) A dual-tumour model was generated by inoculating luciferase-expressing melanoma B16 cell line, B16-Luc, into the brain and under the skin of syngeneic C57BL/6 mice. IF7C(RR)-SN38 was injected intravenously daily at 7.0 μmoles/kg and growth of tumours was assessed by chemiluminescence using an IVIS imager. A similar dual-tumour model was generated with the C6-Luc line in immunocompromised SCID mice. (2) IF7C(RR)-SN38 formulated with 10% Solutol HS15 was injected intravenously daily at 2.5 μmoles/kg into two brain tumour mouse models: B16-Luc cells in C57BL/6 mice, and C6-Luc cells in nude mice. Results (1) Daily IF7C(RR)-SN38 injection suppressed tumour growth regardless of cell lines or mouse strains. (2) Daily injection of Solutol-formulated IF7C(RR)-SN38 led into complete disappearance of B16-Luc brain tumour in C57BL/6 mice, whereas this did not occur in C6-Luc in nude mice. Conclusions IF7C(RR)-SN38 crosses the blood–brain barrier and suppresses growth of brain tumours in mouse models. Solutol HS15-formulated IF7C(RR)-SN38 may have promoted an antitumour immune response.
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Uchibori, Ryosuke, Takashi Okada, Takayuki Ito, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume y Keiya Ozawa. "Retroviral Vector-Producing Mesenchymal Stem Cells for Tumor Tracking and Therapeutic Gene Amplification in Suicide Cancer Gene Therapy." Blood 110, n.º 11 (16 de noviembre de 2007): 1917. http://dx.doi.org/10.1182/blood.v110.11.1917.1917.
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Abstract Mesenchymal stem cells (MSCs) are known to have a tendency to accumulate at the site of tumors, and therefore can be utilized as a platform for targeted delivery of anti-cancer agents. The MSC-based targeted cancer gene therapy can enhance the therapeutic efficacy, because MSCs are considered to reach tumors including metastatic lesions and to deliver therapeutic molecules in a concentrated fashion. This targeted therapy can also reduce systemic adverse side effects, because the anti-cancer agents act locally at the site of tumors without elevating their systemic concentrations. In the present study, we developed genetically-modified MSCs that produce retroviral vectors encoding HSVtk, aiming at augmenting therapeutic efficacy of systemic suicide cancer gene therapy. The tumor tropism and anti-tumor effects of vector-producing MSCs (VP-MSCs) were examined by intravascular injection in tumor-bearing nude mice. MSCs isolated from the bone marrow of SD rats were transfected with plasmid DNA expressing luciferase alone (=non-VP-MSCs) or whole retroviral vector components (LTR-Luc or LTR-HSVtk with Gag-pol and VSV-G) (=VP-MSCs) by nucleofection. To assess tumor tropism of MSCs, nude mice were subcutaneously inoculated with 9L rat glioma cells or Rat-1 fibroblasts, and were subsequently injected with luciferase-expressing MSCs through the left ventricular cavity. The transgene expression was periodically traced by using an in vivo imaging system. As a result, the transgene expression accumulated at the site of subcutaneous 9L tumors, but undetectable at the site of Rat-1 fibroblasts. In addition, the injection of luciferase-expressing VP-MSCs caused much stronger signal of bioluminescence at the site of 9L tumors compared with luciferease-expressing non-VP-MSCs. Immunostaining study showed that luciferase-positive cells (injected MSCs and transduced glioma cells) were detected at the periphery of tumors. To evaluate the therapeutic efficacy, tumor-bearing nude mice were treated with non-VP-MSCs or VP-MSCs combined with HSVtk/GCV system and then the size of subcutaneous tumors was periodically measured. In this model experiments, tumor growth was more efficiently suppressed by injecting VP-MSCs compared with non-VP-MSCs. The present study suggests the effectiveness of VP-MSCs in suicide cancer gene therapy. The therapeutic benefit of this strategy should be further examined in orthotopic and metastatic tumor models.
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Wang, Mengyu, Gunnar Kvalheim, Svein-Ole Mikalsen, Jahn M. Nesland, Gunhild Mælandsmo y Øystein Fodstad. "Bone Marrow Stroma-Derived Mesenchymal Cell Cultures from Nude/Nude Rat Showing Both Ex Vivo Differentiation Properties and High Metastatic Potential in Nude Mice." Blood 104, n.º 11 (16 de noviembre de 2004): 4262. http://dx.doi.org/10.1182/blood.v104.11.4262.4262.
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Abstract Recent studies have revealed that stem cell like cancer cells can be isolated from different types of primary tumor tissue from brain, breast and skin. Such cells have high capability to form tumors when transplanted into experimental animals. Here we describe a newly developed nude rat mesenchymal stem cellS (rMSCs), which spontaneously changed in vivo properties during culturing. Rat bone marrow cells were isolated from the femur and tibia of a male nude/nude rat and cultured in DMEM medium supplemented with 20% bovine fetal serum (FCS). Non- adherent cells were removed after 72 hours of incubation and the adherent bone marrow cells were cultured until a confluent layer appeared. Adherent cells were detached by trypsin, washed and continued to be cultured. After 23 passages by high-density culture the rMSCs spontaneously became more homogenous and formed spheroids in three-dimensional culture. Following ex vivo culturing under different growth conditions these cells were still able to differentiate into fat and neural like cells. The rMSCs also contain high numbers of colony-forming-unit-fibroblasts(cfu-f). The “tumourigenic” growth pattern observed ex vivo prompted us to examine the rMSCs in vivo. Following subcutaneous injection of 1 x106 cells into nude/nude mice a solid tumor appeared under the skin after 12 days. Moreover, intravenous injections and direct injections into left heart ventricle of rMSCs created solid tumors both in the lung, abdominal cavity, bone and skin. Both phenotypic and genetic characterization of early and late passages of the rMSCs and the tumors formed in the mice are being investigated and more details will be presented at the meeting.
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Maawy, Ali, Yong Zhang, Michael Bouvet, Robert M. Hoffman y Ming Zhao. "Salmonella typhimurium A1-R prolongs survival of aggressive pancreatic cancer in orthotopic nude mouse models." Journal of Clinical Oncology 31, n.º 15_suppl (20 de mayo de 2013): e22013-e22013. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22013.
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e22013 Background: Salmonella typhimurium A1-R has been previously shown to target multiple tumor types in various mouse models. The aim of this study was to test the efficacy of S. typhimurium A1-R against a high aggressive pancreatic cell line in an orthotopic nude mouse model. Methods: Human MiaPaCa2 pancreatic cancer cells, expressing red fluorescent protein (RFP), were implanted subcutaneously in nude mice. After tumor engraftment, the mice were subjected to intravenous therapy with S. typhimurium A1-R (5×107 CFU) once a week for 3 weeks. The tumors were harvested and weighed after the treatment period. MiaPaCA2-RFP was subsequently surgically implanted orthotopically and S. typhimurium A1-R treatment was initiated 2 weeks later. Mice were treated with intravenous A1-R (5×107CFU) once a week for 6 weeks, after which survival and tumor growth were recorded. Results: In the subcutaneous tumor model, significant decreases in the rate of tumor growth (p = 0.049) and tumor size (p = 0.004) were observed upon termination. In the orthotopic model, a significant decrease in the rate of tumor growth (p = 0.01) and increased survival was observed (p = 0.014). None of the mice showed any adverse events or weight loss from bacterial therapy. Conclusions: The results suggest further investigation S. typhimurium A1-R, including in combination with chemotherapy, with the goal of cure of pancreatic cancer.
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Thamilarasan, Madhan, William E. Fogler, John L. Magnani y Rahima Zennadi. "Restoration of Normal Blood Flow in Mouse Models of Sickle Cell Vaso-Occlusion Following Intravenous or Subcutaneous Administration of a Highly Potent E-Selectin Specific Inhibitor". Blood 136, Supplement 1 (5 de noviembre de 2020): 17. http://dx.doi.org/10.1182/blood-2020-140276.
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Background: In sickle cell disease (SCD), recurrent episodes of vaso-occlusive crisis (VOC) contribute to morbidity and accelerated mortality. Analysis of the RESET Phase 3 study demonstrated that administration of the pan-selectin inhibitor, rivipansel, early in the course of VOC was associated with efficacy outcomes in favor of rivipansel, suggesting that reversal of vaso-occlusion may be achieved by treatment early in VOC. While both P- and L-selectin likely contribute to the underlying inflammatory cascade leading to VOC, previous studies have shown that E-selectin expression on the vascular luminal surface appears to be crucial for adhesion of sickled (SS)-RBC and leukocytes to the endothelium. GMI-1687 is an innovative potent E-selectin specific antagonist that demonstrates high bioavailability following subcutaneous (SC) administration. In the current investigation, we report on in vitro and in vivo studies evaluating the activity of GMI-1687 in SCD mouse models of VOC. Methods: Townes transgenic mice and nude mice transfused with human SS-RBC were used as in vivo models of SCD. VOC was initiated by TNF injection in both models. Adhesion to inflamed venules and development of VOC was recorded using intravital microscopy at sites of window chamber implants. The in vivo activity of E-selectin inhibition with GMI-1687 was assessed following IV injection in the nude mouse and Townes transgenic models, and SC injection in the nude mouse model of SCD. Results: In an initial study, IV treatment with saline or GMI-1687 was initiated 30 min post infusion of SS-RBC (t30) into TNF-treated mice, a time during which sickle cells are adherent to inflamed venules and VOC has initiated, and repeated 30 minutes later (t60). As expected, mice treated with saline alone showed marked adhesion of human SS-RBC to venules (61% occlusion of the total vessels recorded at t30) with evident blood stasis. Under these conditions, GMI-1687 at 40 μg/kg significantly reversed SS-RBC adhesion and VOC at both t30 and t60 (p=0.002 and 0.0073, respectively, compared to saline treatment). This led to restoration of blood flow in 85% of the venules in GMI-1687 treated mice vs. 18% of vessels with normal blood flow in the control saline treated group. Because of reduced sickle cell adhesion and VOC, the number of circulating SS-RBC increased by approximately 6-fold in mice treated with GMI-1687. Similar anti-adhesive and anti-VOC activities of GMI-1687 treatment were obtained in the Townes transgenic model of SCD where following IV administration of the E-selectin antagonist, adhesion of sickled RBCs was significantly diminished and as a result, the percentage of the total occluded vessel segments was reduced by 80-90%. We next assessed the activity of SC administration with 40 μg/kg GMI-1687 on human SS-RBC adhesion and development of VOC in the nude mouse model. Similar to the IV experiments, GMI-1687 initiated at t30 and t60 post SS-RBC infusion significantly reduced SS-RBC adhesion in inflamed vessels (69% reduction at t30, and 63% at t60, p=0.0001). The reduction in SS-RBC adhesion led to a lower incidence of VOC (2% compared to 30% of vessels in mice injected with saline), and a 5.1-fold improvement (p=0.0315) in the number of circulating human SS-RBC. It is noteworthy that the effective dose of GMI-1687 used in these IV and SC studies resulting in the restoration of normal blood flow was approximately 500-fold less than that reported for rivipansel. Conclusions: These data demonstrate that the administration of the potent and E-selectin specific compound GMI-1687 was effective in restoring blood flow in two mouse models of SCD, and support the development of GMI-1687 formulated for SC use and self-administration with the potential for early intervention of VOC. Disclosures Thamilarasan: GlycoMimetics: Research Funding. Fogler:GlycoMimetics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Magnani:GlycoMimetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zennadi:GlycoMimetics: Research Funding.
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Tanaka, Miwa, Mizuki Homme, Yukari Yamazaki, Keisuke Ae, Seiichi Matsumoto, Subbaya Subramanian y Takuro Nakamura. "Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression". Cancers 12, n.º 2 (30 de enero de 2020): 324. http://dx.doi.org/10.3390/cancers12020324.
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SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by SS18-SSX1 introduction into mesenchymal cells and Tle1 and Atf2 upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. miR-199a2 and miR-214 upregulation within the Dnm3 locus was observed. SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis. miR-214 functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., Cxcl15/IL8). Our results emphasize the role of miR-214 in tumor development and disease progression.
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Protasova, Tatiana P., Anna S. Goncharova, Marina A. Gusareva, Elena A. Karnaukhova, Igor A. Leyman, Anastasia O. Sitkovskaya, A. V. Volkova et al. "Improvement of subcutaneous CDX model of lung cancer using A549 cell line." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e15618-e15618. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15618.
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e15618 Background: Lung cancer is a challenging cancer problem, despite significant progress in its therapy. The search of drugs for the treatment of lung cancer is an urgent task. The creation of animal models of lung cancer plays a key role in preclinical trials and in understanding the mechanisms of tumor pathogenesis. The purpose of the study was to create a subcutaneous cell line-derived xenograft (CDX) model of lung cancer using the human lung cancer cells A459 and to compare results of subcutaneous injections of a cell suspension with different numbers of cells in two groups of animals. Methods: A CDX model of lung cancer was created using the human lung cancer cells A459 and male BALB/c Nude mice divided into two groups (n = 4 and n = 6) with subcutaneous injections of a mix of a cell suspension with Matrigel (200 μl). The injection mix contained 5*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 4) and 10*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 6). Results: Animal models receiving a suspension of 10*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel were characterized by a higher tumor growth index compared to animals receiving 5*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel. Models created with the injections of 10*106 cells showed a larger volume of tumor nodes: 65.33±1, 39.2±1, 41.79±1, 36.64±1, 75.87±1 and 43.13±1 mm3. CDX models created with the injections of 5*106 cells were characterized by a division of the single tumor node by the 30th day of the experiment which complicated the measurement. Conclusions: The creation of a CDX model with injections of 5*106 cells is undesirable due to the nonlinear growth of the xenograft and its division into several tumor nodes. Subcutaneous CDX models of lung cancer created with injections of 10*106 cells showed the linear growth and the formation of the single tumor node.
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Ohashi, M., F. Kanai, H. Ueno, T. Tanaka, K. Tateishi, T. Kawakami, Y. Koike et al. "Adenovirus mediated p53 tumour suppressor gene therapy for human gastric cancer cells in vitro and in vivo". Gut 44, n.º 3 (1 de marzo de 1999): 366–71. http://dx.doi.org/10.1136/gut.44.3.366.
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BACKGROUND/AIMSGastric cancer is one of the most prevalent forms of cancer in East Asia. Point mutation of the p53 gene has been reported in more than 60% of cases of gastric cancer and can lead to genetic instability and uncontrolled cell proliferation. The purpose of this investigation was to evaluate the potential of p53 gene therapy for gastric cancer.METHODSThe responses of human gastric cancer cell lines, MKN1, MKN7, MKN28, MKN45, and TMK-1, to recombinant adenoviruses encoding wild type p53 (AdCAp53) were analysed in vitro. The efficacy of the AdCAp53 treatment for MKN1 and MKN45 subcutaneous tumours in nude mice was assessed in vivo.RESULTSp53-specific growth inhibition was observed in vitro in two of four gastric cancer cell lines with mutated p53, but not in the wild type p53 cell line. The mechanism of the killing of gastric cancer cells by AdCAp53 was found, by flow cytometric analysis and detection of DNA fragmentation, to be apoptosis. In vivo studies showed that the growth of subcutaneous tumours of p53 mutant MKN1 cells was significantly inhibited by direct injection of AdCAp53, but no significant growth inhibition was detected in the growth of p53 wild type MKN45 tumours.CONCLUSIONSAdenovirus mediated reintroduction of wild type p53 is a potential clinical utility in gene therapy for gastric cancers.
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Momiyama, Masashi, Ming Zhao, Hiroaki Kimura, Benjamin Tran, Takashi Chishima, Michael Bouvet, Itaru Endo y Robert M. Hoffman. "Use of tumor-targeting salmonella typhimurium to eradicate human glioma in an orthotopic model in nude mice." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): 2044. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2044.
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2044 Background: Prognosis remains poor for glioma and therefore requires new approaches. We have previously developed a genetically-engineered strain of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012). In the present study, we demonstrated that Salmonella typhimurium A1-R can inhibit and eradicate human glioma in an orthotopic nude mouse model. Methods: S. typhimuirum A1-R was administered by injection through a craniotomy open-window or intravenously in nude mice. To establish the model, 2×105 U87 human glioma cells, expressing red fluorescent protein (RFP), were injected stereotactically into the mouse brain through the craniotomy open window. Two weeks after glioma-cell implantation, mice were treated with S. typhimurium A1-R (2×107 CFU / 200 μl intravenous injection [i.v.] or 1×106 CFU / 1 μl intracranial injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were observed by fluorescence imaging through the craniotomy open window over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor growth 7.6-fold compared with untreated mice (p = 0.009) and improved survival 73% (p = 0.001). Two of ten mice had their tumors eradicated. Intravenous administration of S. typhimurium A1-R was not effective. Conclusions: The results of the present study demonstrate that bacterial therapy of glioma is a novel, effective and safe treatment strategy in a highly treatment-resistance cancer in an orthothopic model, a first step toward clinical development.
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Do, Nghia Minh, Sinh Truong Nguyen, Phuc Hong Vo, Trinh Thi –. Tu Nguyen, Kiet Dinh Truong y Phuc Van Pham. "Establishing murine models of hepatocellular carcinoma using NOD/SCID, nude and Balb/c mice: An initial comparative study". Science and Technology Development Journal 23, n.º 1 (19 de marzo de 2020): 454–60. http://dx.doi.org/10.32508/stdj.v23i1.1767.
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Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality in the world. Therefore, more and more studies are developing novel therapies to treat this disease. The pre-clinical trials on animals are a vital step to evaluate the efficacy as well as side effects of these novel therapies. Hence, this study aimed to develop the murine model of HCC using 3 kinds of mice: NOD/SCID, nude and Balb/c mice.
Methods: HCC cell line HepG2 was used in this study. They were injected into 3 kinds of mice: NOD/SCID, nude and Balb/c mice at three doses: 5 x 106, 2.5 x 106, and 1.25 x 106 cells. Tumor size and body weight of the mice were recorded daily. To confirm these tumors in mice as malignant tumors, they were removed and analyzed by histopathology.
Results: The results showed that in nude mice, the tumors appeared after 1 day of injection and could be detected by the naked eye; they continuously developed until the end of the study. In NOD/SCID mice, the tumors could be detected by the naked eye after 3 days of injection; their sizes also increased until the end of the experimental study. Meanwhile, in Balb/c mice, although the tumors could be observed by the naked eye on the 3rd day after cell injection, they regressed and markedly disappeared after 30 days. The dose of 5 x 106 cells per mouse induced the largest tumors (1.2 cm in diameter) in NOD/SCID mice. The histopathological analysis showed that the tumors collected from nude and NOD/SCID mice also displayed the poorly differentiated malignant carcinoma with muscle tissue invasion.
Conclusion: Both nude and NOD/SCID mice are appropriate for future studies to establish HCC murine models using HepG2 injection.
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Akhter, Javed, Xianghai Chen, Patricia Bowrey, Elaine J. Bolton y David L. Morris. "Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model". Diseases of the Colon & Rectum 40, n.º 3 (marzo de 1997): 317–21. http://dx.doi.org/10.1007/bf02050422.
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Zhang, Caiqin, Yong Zhao, Ningning Zhao, Dengxu Tan, He Zhang, Xue Chen, Hai Zhang, Jiaze An, Changhong Shi y Mengbin Li. "NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye". Contrast Media & Molecular Imaging 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/4979746.
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Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 109/cm2tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide68Ga (68Ga-MHI-148) for PET tracing. We applied the dual-modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and68Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of68Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm × 0.3 cm) and rabbits (1.2 cm × 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC.
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Wang, Ding, Dan Yu, Xueshibojie Liu, Qian Wang, Xuyang Chen, Xindan Hu, Qiong Wang, Chunshun Jin, Lianji Wen y Ling Zhang. "Targeting laryngeal cancer cells with 5-fluorouracil and curcumin using mesoporous silica nanoparticles". Technology in Cancer Research & Treatment 19 (1 de enero de 2020): 153303382096211. http://dx.doi.org/10.1177/1533033820962114.
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Objective: To explore the inhibitory and synergistic effects of 5-fluorouracil and curcumin on Hep-2 laryngeal cancer cells and clarify the effect of mesoporous silica nanoparticles as drug carriers. Methods: The inhibitory effects of 5-fluorouracil and curcumin on Hep-2 cells were detected using the CCK-8 assay. CompuSyn was used to calculate the synergistic effect of the 2 drugs. Flow cytometry was used to detect apoptosis and cell cycle arrest induced by 5-fluorouracil and curcumin. The drugs were loaded into mesoporous nanoparticles. Western blotting was used to detect the expression of related proteins after treatment. The growth of subcutaneous tumors in BALB/c nude after the intraperitoneal injection with drug-loaded mesoporous silica nanoparticles was recorded. Results: 5-Fluorouracil and curcumin synergistically induced apoptosis and cell cycle arrest in Hep-2 cells. Mesoporous silica nanoparticles as drug carriers enhanced the therapeutic effects of 5-fluorouracil and curcumin. Conclusions: Mesoporous silica nanoparticles are expected to be effective drug carriers that enhance the synergistic effects of 5-fluorouracil and curcumin on laryngeal cancer.
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Kim, Ye-Ram, Ah-Reum Han, Jin-Baek Kim y Chan-Hun Jung. "Dendrobine Inhibits γ-Irradiation-Induced Cancer Cell Migration, Invasion and Metastasis in Non-Small Cell Lung Cancer Cells". Biomedicines 9, n.º 8 (3 de agosto de 2021): 954. http://dx.doi.org/10.3390/biomedicines9080954.
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The use of ionizing radiation (IR) during radiotherapy can induce malignant effects, such as metastasis, which contribute to poor prognoses in lung cancer patients. Here, we explored the ability of dendrobine, a plant-derived alkaloid from Dendrobium nobile, to improve the efficacy of radiotherapy in non-small cell lung cancer (NSCLC). We employed Western blotting, quantitative real-time (qRT)-PCR, transwell migration assays, and wound-healing assays to determine the effects of dendrobine on the migration and invasion of A549 lung cancer cells in vitro. Dendrobine (5 mm) inhibited γ-irradiation-induced migration and invasion of A549 cells by suppressing sulfatase2 (SULF2) expression, thus inhibiting IR-induced signaling. To investigate the inhibitory effects of dendrobine in vivo, we established a mouse model of IR-induced metastasis by injecting BALB/c nude mice with γ-irradiated A549 cells via the tail vein. As expected, injection with γ-irradiated cells increased the number of pulmonary metastatic nodules in mice (0 Gy/DPBS, 9.8 ± 1.77; 2 Gy/DPBS, 20.87 ± 1.42), which was significantly reduced with dendrobine treatment (2 Gy/Dendrobine, 10.87 ± 0.71), by prevention of IR-induced signaling. Together, these findings demonstrate that dendrobine exerts inhibitory effects against γ-irradiation-induced invasion and metastasis in NSCLC cells in vitro and in vivo at non cytotoxic concentrations. Thus, dendrobine could serve as a therapeutic enhancer to overcome the malignant effects of radiation therapy in patients with NSCLC.
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Raymond, Karine, Maaike Kreft, Ji-Ying Song, Hans Janssen y Arnoud Sonnenberg. "Dual Role of α6β4 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function". Molecular Biology of the Cell 18, n.º 11 (noviembre de 2007): 4210–21. http://dx.doi.org/10.1091/mbc.e06-08-0720.
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An increased expression of the integrin α6β4 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of α6β4 in the early stages of tumor development. We have isolated cells from mouse skin (mouse tumor-initiating cells [mTICs]) that are deficient in both p53 and Smad4 and carry conditional alleles of the β4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that α6β4 mediates a tumor-suppressive effect. Reconstitution experiments with β4-chimeras showed that this effect is not dependent on ligation of α6β4 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of β4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, α6β4 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector-loop mutants of RasV12 suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, α6β4 can either mediate an adhesion-independent tumor-suppressive effect or act as a tumor promotor.
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Culp, L. A., W. c. Lin, N. Kleinman, K. O'Connor y R. Lechner. "Earliest Steps in Primary Tumor Formation and Micrometastasis Resolved with Histochemical Marker Gene-Tagged Tumor Cells". Microscopy and Microanalysis 3, S2 (agosto de 1997): 31–32. http://dx.doi.org/10.1017/s1431927600007042.
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To facilitate detection of tumor cells at the highest resolution in an athymic nude mouse model system, Balb/c 3T3 cells transformed with the Harvey ras oncogene were transfected with the histochemical marker gene, bacterial lacZ (LZEJ cells). Alternatively, 3T3 cells transformed with the human sis oncogene were transfected with human placental alkaline phosphatase marker gene (APSI cells). Within minutes of subcutaneous injection, these tumor cells could be detected histochemically and the fate of cells followed with time. APSI or LZEJ cells gave very different single-cell morphologies at this site but yielded similar aggregation patterns of cells. Clearance of some cells could readily be detected by diffusion of histochemical product as “curly-haired” organizations of cells condensed into ovoid collections. Expansion of the population occurred with division of many cells in the population, not just one or a few cells. Cell number was quantitated by the development of ultrasensitive luminometry assays for the two histochemical marker enzymes; different kinetics were observed for establishment of LZEJ or APSI cells.
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Loskog, A., C. Ninalga, T. Hedlund, M. Alimohammadi, P.-U. Malmström y T. H. Tötterman. "Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy". Laboratory Animals 39, n.º 4 (1 de octubre de 2005): 384–93. http://dx.doi.org/10.1258/002367705774286475.
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Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting. The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20–40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate. Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.
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Zubeldía-Brenner, Lautaro, Catalina De Winne, Sofía Perrone, Santiago A. Rodríguez-Seguí, Christophe Willems, Ana María Ornstein, Isabel Lacau-Mengido, Hugo Vankelecom, Carolina Cristina y Damasia Becu-Villalobos. "Inhibition of Notch signaling attenuates pituitary adenoma growth in Nude mice". Endocrine-Related Cancer 26, n.º 1 (enero de 2019): 13–29. http://dx.doi.org/10.1530/erc-18-0337.
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Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in Nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36 and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may also be acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors.
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Roux, S., B. Al Sakere, C. Bernat, P. Opolon, J. Garbay, V. Billard, L. Zitvogel, A. Carpentier, L. Mir y C. Robert. "Combining tumor destruction by electrochemotherapy and innate immunity by CpG-ODN: Toward a new combination treatment for melanoma with skin metastases". Journal of Clinical Oncology 24, n.º 18_suppl (20 de junio de 2006): 12507. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.12507.
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12507 Background: Electrochemotherapy (ECT), consisting of electroporating cytotoxic agents (bleomycin or cisplatinum) in tumors, is effective in inducing destruction of cutaneous or subcutaneous tumors and can be used as a palliative treatment for patients with skin melanoma metastases. Our objective was to combine the antigen release induced by ECT with a potent and adapted stimulation of the innate immune system in order to induce a systemic anti-tumor response. Methods: The preclinical work was performed on murine models of skin tumors: fibrosarcoma (LPB) and melanoma (B16F10). We found that electrochemotherapy induced the recruitment of immune cells expressing CD11-c and Mac-1 in the first 48h after the treatment. By quantitative RT-PCR, we showed that this immune cell infiltrate was associated with an increase of TLR9 RNA expression. Therefore, we decided to combine ECT with intra-tumoral injection of TLR9 ligands: unmethylated CpG oligodeoxynucleotides (CpG-ODN). The distant and local antitumoral effect of this association (ECT + CpG-ODN) were tested in mice bearing a tumour on the two flanks (fibrosarcoma or melanoma). Animals were treated on the left flank only by a unique ECT course followed by intratumoral injection of CpG-ODN. Tumor growth rates were monitored on both treated (left) and non-treated (right) sides in order to assess direct and systemic antitumor effects of the association respectively. Experiments were also performed on nude mice, in order to investigate the role of lymphocytes in the systemic antitumor effect. Results: Compared to the separated treatments alone we found an increased local efficacy of the ECT-CpG-ODN, but, more importantly, we demonstrated a clear systemic effect of the combination on the controlateral tumors. In nude mice, no effect was observed in controlateral tumors suggesting a mechanism mediated by T lymphocytes. No significant financial relationships to disclose.
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Endo, Toyoshi y Tetsuro Kobayashi. "Concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to thyrocytes". Endocrine-Related Cancer 20, n.º 6 (4 de septiembre de 2013): 767–76. http://dx.doi.org/10.1530/erc-13-0310.
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A variant located on 14q13.3 nearest to thyroid transcription factor-1 (TTF1) predisposes individuals to thyroid cancer, but whether this variant is related to the RET/PTC rearrangement associated with human papillary thyroid carcinomas (PTCs) is unknown. The aims of this study were to investigate the effects of RET/PTC1 on the expression of thyroid-specific genes in thyrocytes and their relationship with malignant transformation of the thyrocytes. In the absence or presence of TSH, an extracellular signal-regulated kinase was phosphorylated in FRTL5 cells that stably expressed RET/PTC1, and these cells grew independently of TSH. FRTL (RET/PTC1) cells produced 566% more thyroglobulin mRNA and 474% more Na+/I− symporter mRNA than did the control FRTL (pcDNA) cells. FRTL (RET/PTC1) cells expressed 468% more Ttf1 mRNA than did FRTL (pcDNA) cells, but these two cell types did not differ significantly with respect to Pax8 or Ttf2 mRNA levels. When FRTL (RET/PTC1) cells and FRTL (pcDNA), cells were injected into each of nine nude mice, each mouse developed a single tumor at the site of FRTL (RET/PTC1) cell injection; in contrast, tumor formation never occurred at sites of FRTL (cDNA) cells injection. Tumors resulting from FRTL (RET/PTC1) cells retained 125I-uptake activity; moreover, the cells invaded into surrounding skeletal muscle. When overexpression of Ttf1 in FRTL (RET/PTC1) cells was silenced, the cells completely lost their tumorigenic potential. Exogenous TTF1 cDNA enhanced the tumorigenicity of BHP18-21v cells, human PTC cells that express RET/PTC1, in nude mice. These results indicated that concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to FRTL5 and BHP18-21v cells in nude mice.
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Zhao, Jingsong, Gerard Aguilar, Michael Imperiale, Walter Funk y Arie Abo. "rNAPc2, a Novel Inhibitor of Tissue Factor/Factor VIIa Complex, Inhibits Tumor Growth and Metastasis in Mouse Models of Colorectal Cancer." Blood 110, n.º 11 (16 de noviembre de 2007): 923. http://dx.doi.org/10.1182/blood.v110.11.923.923.
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Abstract Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel anti-metastatic, anti-angiogenic, and anti-thrombotic activities. TF is highly expressed in human colorectal tumors and the level of TF expression positively correlates with disease stage and inversely correlates with survival. To explore the therapeutic potential of rNAPc2 during tumor growth and metastasis, we tested rNAPc2 efficacy in experimental colorectal cancers in mice. Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion, as measured by either number of lung surface metastases or lung mass. While rNAPc2 treatment alone moderately reduced primary tumor growth, combining rNAPc2 with the cytotoxic agent 5-fluorouracil (5-FU) resulted in synergistic growth inhibition of HCT116 human colorectal tumor xenografts in nude mice. Likewise, rNAPc2 further reduced tumor growth in HCT116 human colorectal tumor xenograft-bearing mice receiving bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody). Using CD31 and Ki67 immunohistochemisty, we found that rNAPc2 synergized with either 5-FU or bevacizumab in inhibiting microvessel density and tumor cell proliferation in HCT116 human colorectal tumor xenografts. Furthermore, rNAPc2 synergized with CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 human colorectal tumor cells. Long-term administration of rNAPc2 also significantly suppressed formation of intestinal adenomas and adenocarcinomas in ApcMin/+ mice. The dosing regimens of rNAPc2 used in these studies were well tolerated up to a three-month period by recipient mice without major hemorrhage or other adverse effects. In conclusion, the synergistic tumor inhibitory activity of rNAPc2 in pre-clinical colorectal cancer models suggests that rNAPc2 may be an effective anti-tumor agent in human colorectal cancer patients to potentiate chemo- or anti-angiogenic therapies.
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Yuan, Linlin, Xiufen Tian, Yanfei Zhang, Xinhui Huang, Qing Li, Wencai Li y Shenglei Li. "LINC00319 promotes cancer stem cell-like properties in laryngeal squamous cell carcinoma via E2F1-mediated upregulation of HMGB3". Experimental & Molecular Medicine 53, n.º 8 (agosto de 2021): 1218–28. http://dx.doi.org/10.1038/s12276-021-00647-2.
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AbstractLaryngeal squamous cell carcinoma (LSCC) is one of the most common subtypes of head and neck malignancies worldwide. Long intervening/intergenic noncoding RNAs (LINCRNAs) have been recently implicated in various biological processes that take place in the setting of laryngeal cancer, but the regulatory role of LINC00319 in LSCC remains largely unknown. The current study aimed to elucidate the regulatory effect of LINC00319 on the development and progression of LSCC via high-mobility group box 3 (HMGB3). Microarray-based analysis was initially conducted to identify differentially expressed long noncoding RNAs, after which the expression of LINC00319 and HMGB3 in LSCC tissues and cells was determined accordingly. CD133+CD144+ TU177 cells were subsequently isolated and transfected with LINC00319 overexpression vector (oe-LINC00319), short hairpin RNA (sh)-LINC00319, sh-HMGB3, sh-E2F transcription factor 1 (E2F1), and oe-E2F1, as well as their corresponding controls. The proliferative, invasion, self-renewal, and tumorigenic abilities of CD133+CD144+ TU177 cells were then evaluated. Our in vitro findings were further confirmed following subcutaneous injection of cells expressing the corresponding plasmids into nude mice. LINC00319 and HMGB3 expressions were elevated in LSCC cells and tissues. LINC00319 increased HMGB3 expression by recruiting E2F1. Furthermore, the stimulatory role of LINC00319 on the proliferation, invasion, self-renewal ability, and tumorigenicity of CD133+CD144+ TU177 cells was achieved by upregulating HMGB3 via recruitment of E2F1. The in vitro findings were also confirmed by in vivo experiments. Taken together, these data show that downregulating LINC00319 in CD133+CD144+ TU177 cells may serve as a potential anticancer regimen by inhibiting the proliferation and invasion of cancer stem cells in LSCC.
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Pei, Jun, Baohui Han, Minhua Shao y Huifang Sha. "Inhibition of tumor cell growth, invasion, and metastasis by SIM-89, a novel inhibitor of HGF receptor tyrosine kinases." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): e13528-e13528. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13528.
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e13528 Background: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. SIM-89, developed by Simcere Bio-Pharmaceutical Co, Ltd, is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families. Methods: Kinase inhibition was investigated using Z-lyte detection technique(Invitrogen), LanthaScreen Tb-activity technique and LanthaScreen Binding technique. Inhibition of p-Met and Met is validated through Westernblot. IC50 of the compound is determined by CCK-8. HGF level in culture medium is determined by ELISA.Migration and invasion assayare done with Transwell system. A549 and H460(2×106)are implanted subcutaneous in right upper extremity of nude mice.Once daily oral administration of SIM-89/ placebo are given to nude mice for 35d.Tumor growth curve is calculated. B16F10 tumor cells (2 × 105) were implanted via i.v. tail vein injection into mice on day 0. SIM-89/ placebo administration was initiated 3 days after implantation for 10 days followed by assessment of lung tumor burden. Lung nodule diameters were morphometrically measured on digitally captured images. The results for each treatment group (n = 10 animals) were averaged, and statistical t test analysis was done comparing each treatment group to the placebo treated control. Results: SIM-89 is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families,with additional inhibitory activity toward AMPK (A1/B1/G1) and TRKA. SIM-89 significantly decreases HGF level in culture medium of nsclc cell lines at the IC50 of 625nmol/l. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Once daily oral gavage administration of SIM-89 resulted in a dose-dependent reduction in tumor burden, as determined by a reduction in lung wet weights. Conclusions: These data indicate that SIM-89 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion mediated by HGF receptors.