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Edward A. Neuwelt - One of the best experts on this subject based on the ideXlab platform.
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Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models
Neoplasia (New York N.Y.), 2009Co-Authors: Leslie L. Muldoon, Csanad Varallyay, Dana Thomas Dickey, Seth J. Lewin, Edward A. NeuweltAbstract:Abstract The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous Rat xenograft models. Nude Rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased Nude Rat white blood cell counts and glutathione concentRation, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltRation into glioma cell-inoculated Rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltRation. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
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Cyclophosphamide pre-treatment enhances tumor growth in Nude Rat xenografted tumor models
Molecular Cancer Therapeutics, 2007Co-Authors: Leslie L. Muldoon, D Dickey, Csanad Varallyay, Edward A. NeuweltAbstract:C8 For many human tumor cells, tumor growth in immunodeficient Nude Rats can be inconsistent or slow. The objective of this study was to investigate if pre-treatment with the immuno-modulatory chemotherapeutic agent cyclophosphamide (Cytoxan ®) improved tumor growth in intracerebral, metastatic, and subcutaneous Nude Rat xenograft models. Nude Rats were pretreated with cyclophosphamide (100 mg/kg IP) or saline 24hr before tumor cell inoculation. Cell types tested were human ovarian (SKOV3), lung (LX-1), and breast carcinoma (MDA-MB-231BR), B-lymphoma (MC116), and glioma (U87MG and U251). For subcutaneous tumors, 2.5 x 107 cells mixed with matrigel were injected in the left or right flank, and tumor growth was measured by dial caliper. For intracerebral implantation, 106 cells were injected in the caudate nucleus in the right hemisphere, and for intracerebral hematogenous metastases, 106 cells were infused into the right internal carotid artery. Intracerebral tumor growth was monitored by magnetic resonance imaging and histology. In both intracerebral and subcutaneous tumor models, pre-treatment of cyclophosphamide reduced the time delay to tumor detection and increased both tumor volume and the percentage of animals showing tumors. Cyclophosphamide pretreatment increased the number and size of breast cancer brain metastases after intra-arterial injection of breast carcinoma cells. In contrast, cyclophosphamide increased bone and facial, but not brain metastases after intra-arterial injection of lung carcinoma cells. Cyclophosphamide decreased Nude Rat total white blood cell count (45.9 ± 2.9% of baseline on day 1, 30.5 ± 6.3% on day 3), lymphocytes (46.4 ± 7.3% and 54.9 ± 8.9%), and neutrophils (45.7 ± 3.4% and 22.5 ± 4.1%). Blood counts rebounded at day 10 and were back to the baseline at day 21. Our results suggest that cyclophosphamide pre-treatment can enhance xenografted human tumor growth in both intracerebral and subcutaneous models by its immunosuppressive function even in immunodeficient Nude Rats.
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Differential permeability of a human brain tumor xenograft in the Nude Rat: impact of tumor size and method of administRation on optimizing delivery of biologically diverse agents.
Clinical cancer research : an official journal of the American Association for Cancer Research, 1998Co-Authors: Edward A. Neuwelt, Peggy A. Barnett, Christopher I. Mccormick, Robert A. Kroll, Laura G. Remsen, Gary SextonAbstract:To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administRation and tumor size on the distribution of three agents in a Nude Rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v., and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administRation and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administRation of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administRation and BBBD.
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Delivery of herpesvirus and adenovirus to Nude Rat intracerebral tumors after osmotic blood-brain barrier disruption
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Gajanan Nilaver, Leslie L. Muldoon, Robert A. Kroll, Michael A. Pagel, Xandra O. Breakefield, Beverly L. Davidson, Edward A. NeuweltAbstract:Abstract The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the Nude Rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intRatumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstRated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administRation without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administRation of viral vectors may offer a method of global delivery to treat disseminated brain tumors.
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Differential permeability and quantitative MR imaging of a human lung carcinoma brain xenograft in the Nude Rat.
The American journal of pathology, 1995Co-Authors: Peggy A. Barnett, Christopher I. Mccormick, Simon Roman-goldstein, F. Ramsey, Gary Sexton, Jerzy Szumowski, Edward A. NeuweltAbstract:This study characterized agent differential permeability, three-dimensional tumor volume, and survival in an LX-1 human small cell lung carcinoma intracerebral xenograft model in the Nude Rat. The percent accessible tissue space (distribution volume) and the permeability x capillary surface product for aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), dextran 10 (M(r) 10,000), and dextran 70 (M(r) 70,000) were measured between 8 and 16 days after inoculation of tumor. Magnetic resonance imaging and histology were used to quantitate intracerebral tumor volume (mm3). Accessible tissue space (ml/g) and permeability x capillary surface product in intracranial tumor, surrounding brain, and subcutaneous tumor decreased with increasing molecular weight of the agent, regardless of the number of days after inoculation. Accessible tissue space in intracranial tumor increased between 8 and 16 days for all agents except dextran 70. There was little change in the subcutaneous tumor or other tissues with time. Tumor volume calculations from imaging studies correlated with volumetric measurements from histological sections (r2 = 98.5%) and illustRated natural tumor progression (9 to 225 mm3). These results provide a basis for therapeutic design based on differential permeability of specific agents and the ability to quantitatively measure brain tumor volume for accessing tumor response.
Jian Wang - One of the best experts on this subject based on the ideXlab platform.
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A novel GFP Nude Rat model to investigate tumor-stroma interactions
Cancer cell international, 2014Co-Authors: Ning Yang, Bin Huang, Oleg Tsinkalovsky, Narve Brekka, Huaiyang Zhu, Lina Leiss, Per Øyvind Enger, Jian WangAbstract:Backgroud A key stRategy for the study of the tumor microenvironment is to implant human tumor cells in an immunodeficient rodent strain ubiquitously expressing a fluorescent marker. Here, a novel Nude Rat expressing a green fluorescent protein (GFP) transgene was established and engrafted with primary human tumor tissue in order to sepaRate tumor from stromal cell populations for subsequent molecular analysis.
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Development of a new brain metastates model in the Nude Rat
Cancer Research, 2008Co-Authors: Frits Thorsen, Paal-henning Pedersen, Hrvoje Miletic, R. Bjerkvig, Jian WangAbstract:401 Introduction: Animal models are of vital importance in the study of cancer development and progression. The relevance of each model depends on how closely it mimics the histology, physiological parameters, biochemical pathways and metastatic spread of the original tumour. Orthotopic xenografts of human tumours into immunodeficient animals may show similar histological features and metastatic spread as observed in the original tumour. Here we describe a new Rat/tumour model, where brain metastases directly harvested from cancer patients are xenografted into the brains of immunocompromised Rats. Materials and Methods: Brain metastases were collected during opeRation, minced into small fragments, and stereotactically implanted into brains of immunodeficient (Rowett rnu/rnu) Rats. The animals where followed by MR imaging, and T1 weighted (T1w) images (with/without contrast enhancement) as well as T2 weighted (T2w) MR images were acquired using a 7T small animal MR scanner. As tumours developed, diffusion weighted images were also acquired. The Rats where sacrificed upon signs of illness, and detailed histological examinations of the tumours were performed. Results and Discussion: Brain metastases from several different patients were implanted (primary: colon, ovarian, lung), and all developed tumours in the Rat brain after 6-32 weeks. T1w images after contrast injections of colon metastases and ovarian metastases in the Rat brains showed similar contrast enhancement to the clinical pictures. T2w images displayed extensive edema inside the tumour area. Diffusion weighted imaging of the colon metastases in the Rat brains further verified the increased intRatumoral edema, and the apparent diffusion constant increased from 0.682*10-3 mm2/sec (control animals) to 0.947*10-3 mm2/sec (p
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Human glioblastoma biopsy spheroids xenografted into the Nude Rat brain show growth inhibition after stereotactic radiosurgery
Journal of Neuro-Oncology, 2007Co-Authors: Frits Thorsen, Per Øyvind Enger, Jian Wang, Rolf Bjerkvig, Paal-henning PedersenAbstract:Background The Gamma Knife is currently used to boost treatment of malignant gliomas. However, few experimental studies have focused on its radiobiological effects. In this work, the growth and invasiveness of human glioblastoma spheroids xenografted into Nude Rat brains were assessed after radiosurgery. Temporary in vitro as well as long-term in vivo radiation effects were studied. Methods Glioblastoma biopsy spheroids were irradiated with 12 or 24 Gy. Short-term in vitro spheroid viability and tumour cell migRation was determined by microscopic techniques. Pre-irradiated glioblastoma spheroids were implanted into brains of immunosuppressed Rats. Long-term tumour development was assessed by magnetic resonance (MR) imaging, and animal survival was recorded. An immunohistochemical analysis was performed on the sectioned Rat brains. Results Both un-irradiated and irradiated spheroids remained viable during 2 months in culture, but a dose-dependent inhibition of tumour growth and migRation was seen. MR imaging 4 weeks after implantation also showed a dose-dependent inhibition in tumour development. Median animal survival times were 25.5 days (control group), 43 days (12 Gy group) and 96 days (24 Gy group). The study of in vivo long-term radiation effects on the remaining viable tumour population showed no difference in Ki-67 labelling index and microvascular density before and after radiosurgery. Conclusions A dose-dependent inhibition of tumour growth and invasion, as well as a dose-dependent increase in animal survival was observed. The model system described is well suited for assessing the radiobiological effects of Gamma Knife radiosurgery. The results indicate that radiosurgery of malignant gliomas might be effective in controlling tumour progression in selected glioblastoma patients.
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Human glioblastoma biopsy spheroids xenografted into the Nude Rat brain show growth inhibition after stereotactic radiosurgery.
Journal of neuro-oncology, 2006Co-Authors: Frits Thorsen, Per Øyvind Enger, Jian Wang, Rolf Bjerkvig, Paal-henning PedersenAbstract:Background The Gamma Knife is currently used to boost treatment of malignant gliomas. However, few experimental studies have focused on its radiobiological effects. In this work, the growth and invasiveness of human glioblastoma spheroids xenografted into Nude Rat brains were assessed after radiosurgery. Temporary in vitro as well as long-term in vivo radiation effects were studied.
Øystein Fodstad - One of the best experts on this subject based on the ideXlab platform.
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Characterization of a Bone Marrow Derived Mesenchymal Cell Line from Nude Rat Assembling Tumor Stem/Progenitor Cell Properties In Vitro and In Vivo.
Blood, 2006Co-Authors: Mengyu Wang, Svein-ole Mikalsen, Jahn M. Nesland, Gunhild Mari Mælandsmo, Øystein Fodstad, Stein Saeboe-larssen, Elena Olsen, Gunnar KvalheimAbstract:Here we report the in vitro and in vivo properties of a spontaneously transformed Nude Rat mesenchymal stem cells (rTMSCs) following culture passages 23. When this cell line was compared with early passages of mesenchymal cells (rMSCs) from the same animal, no apparent differences could be seen with regard to the phenotype and Gap junctions’ connexin 43. However, the telomerase activity in rTMSCs is lower than in the rMSCs. Karyotyping of rTMSC gave a trisome 6 phenotype. Microarry analysis of rTMSC shows over expression of the transforming growth factor family including TGF-beta and BMp6. Both rMSC and rTMSC had equal capability to differentiate into adipocytic and “neural like” linage. In contrast rTMSC was unable to differentiate into bone and only this cell line form spheroids in cultures. Subcutaneously injection of rTMSC in doses down to 2x 104 into Nude/Nude mice formed tumor in all animals tested. Examination of the tumor assembles morphology like an immature sarcoma. When 100–200 SP + cells were administered to the animals, tumor could also be formed. After intravenous injections and direct injections into left heart ventricle all animals developed metastasis in the lung; abdominal cavity; bone and skin. The rTMSC has been stabled marked with reporter gene GFP and Leucipherase. Currently the prolifeRation and migRation capacity of the linage-differentiated rTMSC is studied in vivo by imaging and these results will be presented. We conclude that our normal and transformed rMSCs could be potential useful for further biological studies on mesenchymal cells both in vitro and in vivo.
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characterization of a bone marrow derived mesenchymal cell line from Nude Rat assembling tumor stem progenitor cell properties in vitro and in vivo
Blood, 2006Co-Authors: Mengyu Wang, Svein-ole Mikalsen, Jahn M. Nesland, Gunhild Mari Mælandsmo, Øystein Fodstad, Elena Olsen, Stein Saeboelarssen, Gunnar KvalheimAbstract:Here we report the in vitro and in vivo properties of a spontaneously transformed Nude Rat mesenchymal stem cells (rTMSCs) following culture passages 23. When this cell line was compared with early passages of mesenchymal cells (rMSCs) from the same animal, no apparent differences could be seen with regard to the phenotype and Gap junctions’ connexin 43. However, the telomerase activity in rTMSCs is lower than in the rMSCs. Karyotyping of rTMSC gave a trisome 6 phenotype. Microarry analysis of rTMSC shows over expression of the transforming growth factor family including TGF-beta and BMp6. Both rMSC and rTMSC had equal capability to differentiate into adipocytic and “neural like” linage. In contrast rTMSC was unable to differentiate into bone and only this cell line form spheroids in cultures. Subcutaneously injection of rTMSC in doses down to 2x 104 into Nude/Nude mice formed tumor in all animals tested. Examination of the tumor assembles morphology like an immature sarcoma. When 100–200 SP + cells were administered to the animals, tumor could also be formed. After intravenous injections and direct injections into left heart ventricle all animals developed metastasis in the lung; abdominal cavity; bone and skin. The rTMSC has been stabled marked with reporter gene GFP and Leucipherase. Currently the prolifeRation and migRation capacity of the linage-differentiated rTMSC is studied in vivo by imaging and these results will be presented. We conclude that our normal and transformed rMSCs could be potential useful for further biological studies on mesenchymal cells both in vitro and in vivo.
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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, 2004Co-Authors: Mengyu Wang, Gunnar Kvalheim, Svein-ole Mikalsen, Jahn M. Nesland, Gunhild Mari Mælandsmo, Øystein FodstadAbstract: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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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, 2004Co-Authors: Mengyu Wang, Gunnar Kvalheim, Svein-ole Mikalsen, Jahn M. Nesland, Gunhild Mari Mælandsmo, Øystein FodstadAbstract: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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Growth of precultured human glioma specimens in Nude Rat brain.
Journal of neurosurgery, 1999Co-Authors: Olav Engebraaten, Geir Olav Hjortland, Henry Hirschberg, Øystein FodstadAbstract:Object. The aim of this study was to develop an improved animal model for brain tumor study. The need for better and more relevant brain tumor models is generally acknowledged. Glioma tissue can be cultured directly from the biopsy specimen as tumor spheroids. Using such precultured tissue, a new in vivo model for studying human gliomas was established. Methods. Precultured small tumor spheroids (< 300 µm) prepared from cell lines or tumor biopsy fragments were injected into the brains of immunodeficient Rats by using a 5-µl Hamilton syringe that had a piston in the needle. Tumors could be established by injecting a single spheroid derived from the U-87MG cell line, whereas inoculation of 10 spheroids resulted in a tumor take comparable to that attained with injection of 106 single cells. Biopsy specimens obtained from six patients who underwent surgery for glioblastoma multiforme were cultured as organotypic spheroids for 11 to 18 days before inoculation into the Rats. The animals were killed 3 months af...
Leslie L. Muldoon - One of the best experts on this subject based on the ideXlab platform.
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Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models
Neoplasia (New York N.Y.), 2009Co-Authors: Leslie L. Muldoon, Csanad Varallyay, Dana Thomas Dickey, Seth J. Lewin, Edward A. NeuweltAbstract:Abstract The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous Rat xenograft models. Nude Rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased Nude Rat white blood cell counts and glutathione concentRation, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltRation into glioma cell-inoculated Rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltRation. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
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Cyclophosphamide pre-treatment enhances tumor growth in Nude Rat xenografted tumor models
Molecular Cancer Therapeutics, 2007Co-Authors: Leslie L. Muldoon, D Dickey, Csanad Varallyay, Edward A. NeuweltAbstract:C8 For many human tumor cells, tumor growth in immunodeficient Nude Rats can be inconsistent or slow. The objective of this study was to investigate if pre-treatment with the immuno-modulatory chemotherapeutic agent cyclophosphamide (Cytoxan ®) improved tumor growth in intracerebral, metastatic, and subcutaneous Nude Rat xenograft models. Nude Rats were pretreated with cyclophosphamide (100 mg/kg IP) or saline 24hr before tumor cell inoculation. Cell types tested were human ovarian (SKOV3), lung (LX-1), and breast carcinoma (MDA-MB-231BR), B-lymphoma (MC116), and glioma (U87MG and U251). For subcutaneous tumors, 2.5 x 107 cells mixed with matrigel were injected in the left or right flank, and tumor growth was measured by dial caliper. For intracerebral implantation, 106 cells were injected in the caudate nucleus in the right hemisphere, and for intracerebral hematogenous metastases, 106 cells were infused into the right internal carotid artery. Intracerebral tumor growth was monitored by magnetic resonance imaging and histology. In both intracerebral and subcutaneous tumor models, pre-treatment of cyclophosphamide reduced the time delay to tumor detection and increased both tumor volume and the percentage of animals showing tumors. Cyclophosphamide pretreatment increased the number and size of breast cancer brain metastases after intra-arterial injection of breast carcinoma cells. In contrast, cyclophosphamide increased bone and facial, but not brain metastases after intra-arterial injection of lung carcinoma cells. Cyclophosphamide decreased Nude Rat total white blood cell count (45.9 ± 2.9% of baseline on day 1, 30.5 ± 6.3% on day 3), lymphocytes (46.4 ± 7.3% and 54.9 ± 8.9%), and neutrophils (45.7 ± 3.4% and 22.5 ± 4.1%). Blood counts rebounded at day 10 and were back to the baseline at day 21. Our results suggest that cyclophosphamide pre-treatment can enhance xenografted human tumor growth in both intracerebral and subcutaneous models by its immunosuppressive function even in immunodeficient Nude Rats.
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Delivery of herpesvirus and adenovirus to Nude Rat intracerebral tumors after osmotic blood-brain barrier disruption
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Gajanan Nilaver, Leslie L. Muldoon, Robert A. Kroll, Michael A. Pagel, Xandra O. Breakefield, Beverly L. Davidson, Edward A. NeuweltAbstract:Abstract The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the Nude Rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intRatumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstRated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administRation without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administRation of viral vectors may offer a method of global delivery to treat disseminated brain tumors.
Ho Taek Song - One of the best experts on this subject based on the ideXlab platform.
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18F-fluoride PET imaging in a Nude Rat model of bone metastasis from breast cancer: Comparison with 18F-FDG and bioluminescence imaging
Nuclear medicine and biology, 2015Co-Authors: Won Jun Kang, Eun Hye Song, Jun Young Park, Young Jin Park, Arthur Cho, Ho Taek SongAbstract:Abstract Introduction Clinically-relevant animal models and appropriate imaging diagnostic tools are essential to study cancer and develop novel therapeutics. We evaluated a model of bone metastasis in Nude Rats by micro-PET and bioluminescence imaging. Methods A bone metastasis model was produced by intracardiac injection of osteotropic MDA-MB-231Bo-Luc human breast cancer cells into Nude Rats. Bioluminescence imaging and micro-PET scans using 18 F-FDG and 18 F-fluoride were acquired serially for 5weeks. We correlated bioluminescence imaging, 18 F-FDG and 18 F-fluoride PET images, and histological slides. Results Multiple bone metastases were successfully evaluated by bioluminescence imaging and 18 F-FDG and 18 F-fluoride PET scans. Bioluminescence photon flux increased exponentially on weekly follow-up. 18 F-FDG PET revealed increased FDG uptake at the spine and bilaterally in the hind legs in week 2 images, and showed a progressive pattern up to 4weeks that correlated with bioluminescence imaging. 18 F-fluoride PET showed minimal abnormal findings in week 2 images, but it showed an irregular pattern at the spine from week 3 or 4 images. On quantitative analysis with standardized uptake values, a pattern of gradual increase was observed from week 2 to week 4 in both 18 F-FDG PET and fluoride PET. Histopathological examination confirmed the formation of osteolytic metastasis and necrosis of the distal femur, which appeared as a photon defect on PET scans. Conclusion Developing bone metastasis from breast cancer in a Nude Rat model was successfully evaluated with an animal PET imaging system and bioluminescence imaging. This Nude Rat model of bone metastasis, which can be evaluated by PET imaging, may be a valuable tool for evaluating early responses to novel therapeutics.
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quantitative t2 imaging of metastatic human breast cancer to brain in the Nude Rat at 3 t
NMR in Biomedicine, 2011Co-Authors: Ho Taek Song, Elaine K. Jordan, Bobbi K. Lewis, Eric M. Gold, Wei Liu, Joseph A. FrankAbstract:This study uses quantitative T2* imaging to track ferumoxides-protamine sulfate (FEPro) labeled MDA-MB-231BRL human breast cancer cells (231BRL) that metastasize to the Nude Rat brain. Four cohorts of Nude Rats were intracardiac (IC) injected with either FEPro labeled, unlabeled, TRIAL treated (to induce apoptosis) 231BRL cells or saline in order to develop metastatic breast cancer in the brain. The Rat heads were imaged serially over 3-4 weeks using a gradient multi-echo and turbo spin echo pulse sequences at 3 Tesla with a solenoid receive only 4cm diameter coil. Quantitative T2* maps of whole brain were obtained by applying single exponential fitting to the signal intensity of T2* images and the distribution of T2* values in brain voxels were calculated. MRI findings were correlated with Prussian blue (PB) stain and immunohistochemical stain for iron in breast cancer and macrophages. Quantiative analysis of T2* from the brain voxels demonstRated a significant shift to lower values following IC injection of FEPro labeled 231BRL cells as compared to animals that received unlabeled cells or apoptotic cells or saline. Quartile analysis based on the T2* distribution obtained from brain voxels demonstRated significant differences (p<0.0083) in number of voxels with T2* values between 10-35 (Q1), 36-60 (Q2) and 61-86 (Q3) milliseconds from day 1 to 3 weeks post infusion of labeled 231BRL cells compared to baseline scans. There was no significant differences in the distribution of T2* obtained from serial MRI in Rats receiving unlabeled or TRIAL treated cells or saline. Histological analysis demonstRated isolated PB positive breast cancer cells scattered in brains of Rats that received labeled cells compared to animals that received unlabeled or apoptotic cells. Quantitative T2* analysis of FEPro labeled metastasized cancer cells was possible even after the hypointense voxels are no longer visible on T2*-weighted images.
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Quantitative T2* imaging of metastatic human breast cancer to brain in the Nude Rat at 3 T
NMR in biomedicine, 2010Co-Authors: Ho Taek Song, Elaine K. Jordan, Bobbi K. Lewis, Eric M. Gold, Wei Liu, Joseph A. FrankAbstract:This study uses quantitative T2* imaging to track ferumoxides-protamine sulfate (FEPro) labeled MDA-MB-231BRL human breast cancer cells (231BRL) that metastasize to the Nude Rat brain. Four cohorts of Nude Rats were intracardiac (IC) injected with either FEPro labeled, unlabeled, TRIAL treated (to induce apoptosis) 231BRL cells or saline in order to develop metastatic breast cancer in the brain. The Rat heads were imaged serially over 3-4 weeks using a gradient multi-echo and turbo spin echo pulse sequences at 3 Tesla with a solenoid receive only 4cm diameter coil. Quantitative T2* maps of whole brain were obtained by applying single exponential fitting to the signal intensity of T2* images and the distribution of T2* values in brain voxels were calculated. MRI findings were correlated with Prussian blue (PB) stain and immunohistochemical stain for iron in breast cancer and macrophages. Quantiative analysis of T2* from the brain voxels demonstRated a significant shift to lower values following IC injection of FEPro labeled 231BRL cells as compared to animals that received unlabeled cells or apoptotic cells or saline. Quartile analysis based on the T2* distribution obtained from brain voxels demonstRated significant differences (p
