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Michael R Johnston - One of the best experts on this subject based on the ideXlab platform.
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early combined treatment with carboplatin and the mmp inhibitor prinomastat prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung Cancer Model
Lung Cancer, 2003Co-Authors: Jiang Liu, David R Shalinsky, Mingsound Tsao, Marco Pagura, Rama Khoka, Jim Fata, Michael R JohnstonAbstract:We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung Cancer Model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and prinomastat commenced when the primary lung Cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with prinomastat. Our results suggest that the administration of prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung Cancer (NSCLC) patients.
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characterization of a highly metastatic orthotopic lung Cancer Model in the nude rat
Clinical & Experimental Metastasis, 1999Co-Authors: Michael R Johnston, Randy B Howard, John B M Mullen, Marco E PaguraAbstract:The prevailing subcutaneous nude rodent tumor xenograft Models used for biological and preclinical studies do not optimally reflect some important biological properties of Cancer, especially invasion and metastasis. Orthotopic Models have been developed to address this need. However, for lung Cancer none of the available Models are optimal, in that none originate from an orthotopic (bronchial) primary site and exhibit extensive extrathoracic metastasis. Our goal was to develop a consistent rodent Model of non-small cell lung Cancer with both of these properties. Groups of male Rowett nude rats were given 500 rads of gamma radiation and then endobronchially implanted in the right caudal lobe airway with 50 mg of small NCI-H460 tumor fragments taken from an orthotopic donor tumor. They were then sacrificed at selected post-implantation times and evaluated grossly and histologically for animal weight, primary tumor take and size, and metastatic tumor incidence at multiple sites. At a late time point (32–35 days), consistency of primary tumor size and metastasis was estimated by comparing results from four groups of rats implanted on different occasions. The results showed that the primary tumors grew steadily, reaching four grams by days 32–35. Rats gained weight until days 14 to 21, but then began to show cachexia. High metastatic rates (>60%) were seen for mediastinal lymph nodes (by 21 days), and kidney, bone and brain (by 28 days). Mean primary tumor size and the incidences of both regional and systemic metastasis were consistent at 32–35 days in four different groups of six animals. In conclusion, this orthotopic lung Cancer Model is highly metastatic and consistent in terms of both primary tumor growth and metastatic behavior. It is the only available rodent Model of human lung Cancer emanating from an endobronchial site and metastasizing to multiple extrapulmonary sites, and should be very useful for both biological and preclinical studies of lung Cancer, particularly where studies of antimetastatic activity are of interest, and/or where survival studies are desired.
Michael Goldberg - One of the best experts on this subject based on the ideXlab platform.
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decitabine enhances lymphocyte migration and function and synergizes with ctla 4 blockade in a murine ovarian Cancer Model
Cancer immunology research, 2015Co-Authors: Lei Wang, Sandra Orsulic, Zohreh Amoozgar, Jing Huang, Mohammad H Saleh, Deyin Xing, Michael GoldbergAbstract:The lack of second-line treatment for relapsed ovarian Cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian Cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian Cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian Cancer Model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8(+) T cells, promotes their production of IFNγ and TNFα, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this Model, the efficacy of anti-CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs cytotoxic lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian Cancer.
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decitabine enhances lymphocyte migration and function and synergizes with ctla 4 blockade in a murine ovarian Cancer Model
Cancer immunology research, 2015Co-Authors: Lei Wang, Sandra Orsulic, Zohreh Amoozgar, Jing Huang, Mohammad H Saleh, Deyin Xing, Michael GoldbergAbstract:The lack of second-line treatment for relapsed ovarian Cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian Cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian Cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian Cancer Model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8+ T cells, promotes their production of IFNγ and TNFα, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this Model, the efficacy of anti–CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs cytotoxic lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian Cancer. Cancer Immunol Res; 3(9); 1030–41. ©2015 AACR .
Chunmei Zhao - One of the best experts on this subject based on the ideXlab platform.
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Cancer immunoediting from immunosurveillance to tumor escape in microvillus formed niche a study of syngeneic orthotopic rat bladder Cancer Model in comparison with human bladder Cancer
Neoplasia, 2010Co-Authors: Carljorgen Arum, Endre Anderssen, Trond Viset, Yosuke Kodama, Steinar Lundgren, Duan Chen, Chunmei ZhaoAbstract:Cancer cells can develop an attenuated immunogenicity and/or create an immunosuppressive microenvironment to prevent tumor eradication by host immune system, the so-called “Cancer immunoediting” hypothesis. The aim of the present study was to find evidence for this hypothesis by using a rat orthotopic bladder Cancer Model. Fisher rats were inoculated with AY-27 cells (a Fisher rat bladder Cancer cell line). Cultured Cancer cells, rat and human bladder Cancer tissues, and publicly available microarray data from human bladder Cancer were analyzed by means of bioinformatics and morphology. Results showed that 12 of 24 differentially expressed pathways were concordant in connection to cell cycle and proliferation between rats and humans (both non-muscle-invasive and muscle-invasive tumors) and that 11 of the 24 pathways, including major histocompatibility complex, were related to host immunosurveillance with activations of T cells and natural killer cells in rats. The altered pathways and morphogenesis of this rat Model corresponded more closely with those of human muscle-invasive rather than non-muscle-invasive tumors. A unique ultrastructure displaying microvillus-formed niches was found in small areas within the tumor of both rats and humans. These niches were interconnected with desmosomes between Cancer cells and without infiltration of lymphocytes. The expression of E-cadherin, selectins, PGP9.5, vascular endothelial growth factor, caspase-3, CD133, Oct-4, nestin, CD3, and CD45RA was lower in the tumor than in the adjacent normal epithelium. We suggest that the microvillus-formed niche that harbors a few implanted Cancer cells might be the compartment that prevents the tumor eradication by the host immune system.
John W Greiner - One of the best experts on this subject based on the ideXlab platform.
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abstract 1480 systemic immunotherapeutic efficacy of an immunocytokine nhs muil12 in a superficial murine orthotopic bladder Cancer Model
Cancer Research, 2016Co-Authors: Amanda J Vandeveer, Jeffrey Schlom, John W GreinerAbstract:Interleukin-12 (IL-12) is one of the most powerful proinflammatory cytokines capable of supporting T and NK cell function, inducing interferon-gamma while driving a TH1 adaptive immune response. Yet, to date, its success as an antitumor agent in many preclinical Models has yet to be realized in a clinical setting due to systemic toxicity. Investigators have developed IL-12 delivery systems to maximize deposition of the cytokine directly in the tumor microenvironment that may be the preferred site for IL-12 while mitigating the dose-limiting systemic effects. Here we describe a novel immunocytokine, NHS-IL12, consisting of two molecules of human (hu) or murine (mu) IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). NHS76 recognizes exposed chromatin-DNA often found in human/murine tumors that have outpaced their blood vessels and the inadequate perfusion quickly results in tumor necrosis. Indeed, previous studies have shown selective tumor uptake of NHS-IL12 in necrotic subcutaneous murine tumors. In the present study, we evaluated the use of NHS-muIL12 in a murine orthotopic bladder Cancer Model (MB49 Luc). MB49 luciferase positive cells, instilled into the bladder form superficial, multifocal tumors which can be monitored in real time with a luciferase-based intravital imaging system. Urothelial bladder Cancer is known to respond favorably to immunotherapeutic agents due to the presence of multiple somatic mutations, a high number of TILs, and a response to the live bacterium Bacillus Calmette-Guerin (BCG). NHS-muIL12 was found to be a very potent anti-tumor agent in both subcutaneous and intravesical MB49 tumor Models, reducing tumor volume in a dose-dependent manner. For example, in the intravesical bladder Model, antitumor effects were initially seen at 2.5 ug/kg administrated as three separate systemic injections. Mice were completely cured of their bladder tumors when treated at 20 ug/kg x 3 NHS-muIL12 injections with durable tumor-free long-term survival. Immune analyses revealed potent p15E-specific CTLs and IFN-γ responses, indicating the development of a specific anti-tumor immune response in mice treated with NHS-muIL12. Underlying the durable tumor-free long-term survival was an immune memory response that protected mice following re-challenge with either subcutaneous or intravesical MB49 tumor cells. Anti-tumor efficacy required the presence of NK or CD8+ T cells as depletion of either abrogated the anti-tumor effects of this agent. NHS-huIL12, is currently being evaluated against solid tumors, in a Phase 1 clinical trial (NCT01417546). We acknowledge the kind contribution of NHS-muIL12 from EMD Serono, Billerica, MA. Citation Format: Amanda J. Vandeveer, Jeffrey Schlom, John W. Greiner. Systemic immunotherapeutic efficacy of an immunocytokine, NHS-muIL12, in a superficial murine orthotopic bladder Cancer Model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1480.
Kesavan Esuvaranathan - One of the best experts on this subject based on the ideXlab platform.
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nonviral cytokine gene therapy on an orthotopic bladder Cancer Model
Clinical Cancer Research, 2003Co-Authors: Ratha Mahendran, Kesavan EsuvaranathanAbstract:Purpose: The purpose is to assess cytokine gene transfection in tumor cells and its therapeutic efficacy in an orthotopic mouse bladder Cancer Model after liposome-mediated gene transfer. Experimental Design: A total of 1 × 10 5 MB49 cells was instilled into the bladder of C57BL/6 mice after electrocautery to establish the tumor Model. The plasmids were constructed by inserting the coding sequences for murine IFN-α1 and granulocyte macrophage colony-stimulating factor into a plasmid vector pBudCE4.1. Transient transfection was performed using a cationic lipid N- [1-(2,3-dioleoyloxyl)propyl] -N,N,N- trimethylammoniummethyl sulfate and methyl-β-cyclodextrin-solubilized cholesterol. The in vitro expression of cytokines was checked by ELISA. The expression of the transgene in situ was confirmed by immunohistochemistry and 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside staining. Mice bearing orthotopic tumors were treated with plasmid DNA/liposome complex by intravesical instillation twice a week for 3 weeks. Results: Superficial bladder tumors were established by intravesical instillation of MB49 into cauterized bladders. The expression level of cytokines in transfected cell lines was increased significantly. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/ N- [1-(2,3-dioleoyloxyl)propyl] -N,N,N- trimethylammoniummethyl sulfate/methyl-β-cyclodextrin-solubilized cholesterol after a single 2 h in situ transfection. The tumor incidence in the treatment groups was dramatically decreased from 76.9% in the control group to 15.4–30.8% in the treatment groups. Conclusions: We demonstrated in the orthotopic mouse bladder Cancer Model that successful inhibition of tumor cell growth could be obtained with cytokine gene therapy. The results suggest that our liposome transfection system appears to be a promising method for gene therapy of bladder Cancer in vivo .
