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Article ; Online: Phosgene: toxicology, animal models, and medical countermeasures.

Hobson, Stephen T / Richieri, Richard A / Parseghian, Missag H

2021 Volume 31, Issue 4, Page(s) 293–307

Abstract: Phosgene is a gas crucial to industrial chemical processes with widespread production (∼1 million tons/year in the USA, 8.5 million tons/year worldwide). Phosgene's high toxicity and physical properties resulted in its use as a chemical warfare agent ... ...

Abstract	Phosgene is a gas crucial to industrial chemical processes with widespread production (∼1 million tons/year in the USA, 8.5 million tons/year worldwide). Phosgene's high toxicity and physical properties resulted in its use as a chemical warfare agent during the First World War with a designation of CG ('Choky Gas'). The industrial availability of phosgene makes it a compound of concern as a weapon of mass destruction by terrorist organizations. The hydrophobicity of phosgene exacerbates its toxicity often resulting in a delayed toxidrome as the upper airways are moderately irritated; by the time symptoms appear, significant damage has occurred. As the standard of care for phosgene intoxication is supportive therapy, a pressing need for effective therapeutics and treatment regimens exists. Proposed toxicity mechanisms for phosgene based on human and animal exposures are discussed. Whereas intermediary components in the phosgene intoxication pathways are under continued discussion, generation of reactive oxygen species and oxidative stress is a common factor. As animal models are required for the study of phosgene and for FDA approval via the Animal Rule; the status of existing models and their adherence to Haber's Rule is discussed. Finally, we review the continued search for efficacious therapeutics for phosgene intoxication; and present a rapid post-exposure response that places exogenous human heat shock protein 72, in the form of a cell-penetrating fusion protein (Fv-HSP72), into lung tissues to combat apoptosis resulting from oxidative stress. Despite significant progress, additional work is required to advance effective therapeutics for acute phosgene exposure.
MeSH term(s)	Animals ; Chemical Warfare Agents/toxicity ; Humans ; Lung/drug effects ; Medical Countermeasures ; Models, Animal ; Phosgene/toxicity
Chemical Substances	Chemical Warfare Agents ; Phosgene (117K140075)
Language	English
Publishing date	2021-02-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2081252-8
ISSN	1537-6524 ; 1537-6516 ; 1051-7235
ISSN (online)	1537-6524
ISSN	1537-6516 ; 1051-7235
DOI	10.1080/15376516.2021.1885544
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Article ; Online: Targeted heat shock protein 72 for pulmonary cytoprotection.

Parseghian, Missag H / Hobson, Stephen T / Richieri, Richard A

Annals of the New York Academy of Sciences

2016 Volume 1374, Issue 1, Page(s) 78–85

Abstract: Heat shock protein 72 (HSP72) is perhaps the most important member of the HSP70 family of proteins, given that it is induced in a wide variety of tissues and cells to combat stress, particularly oxidative stress. Here, we review independent observations ... ...

Abstract	Heat shock protein 72 (HSP72) is perhaps the most important member of the HSP70 family of proteins, given that it is induced in a wide variety of tissues and cells to combat stress, particularly oxidative stress. Here, we review independent observations of the critical role this protein plays as a pulmonary cytoprotectant and discuss the merits of developing HSP72 as a therapeutic for rapid delivery to cells and tissues after a traumatic event. We also discuss the fusion of HSP72 to a cell-penetrating single-chain Fv antibody fragment derived from mAb 3E10, referred to as Fv-HSP70. This fusion construct has been validated in vivo in a cerebral infarction model and is currently in testing as a clinical therapeutic to treat ischemic events and as a fieldable medical countermeasure to treat inhalation of toxicants caused by terrorist actions or industrial accidents.
MeSH term(s)	Animals ; Cytoprotection ; HSP72 Heat-Shock Proteins/genetics ; HSP72 Heat-Shock Proteins/metabolism ; Humans ; Lung/cytology ; Lung/metabolism ; Models, Biological ; Molecular Targeted Therapy ; Stress, Physiological
Chemical Substances	HSP72 Heat-Shock Proteins
Language	English
Publishing date	2016-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	211003-9
ISSN	1749-6632 ; 0077-8923
ISSN (online)	1749-6632
ISSN	0077-8923
DOI	10.1111/nyas.13059
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Article ; Online: Development of an acute, short-term exposure model for phosgene.

Hobson, Stephen T / Casillas, Robert P / Richieri, Richard A / Nishimura, Robert N / Weisbart, Richard H / Tuttle, Rick / Reynolds, Glenn T / Parseghian, Missag H

Toxicology mechanisms and methods

2019 Volume 29, Issue 8, Page(s) 604–615

Abstract: Phosgene is classified as a chemical warfare agent, yet data on its short-duration high concentration toxicity in a nose-only exposure rat model is sparse and inconsistent. Hence, an exposure system for short-term/high concentration exposure was ... ...

Abstract	Phosgene is classified as a chemical warfare agent, yet data on its short-duration high concentration toxicity in a nose-only exposure rat model is sparse and inconsistent. Hence, an exposure system for short-term/high concentration exposure was developed and characterized. Herein, we report the median lethal concentration (LC
MeSH term(s)	Animals ; Chemical Warfare Agents/toxicity ; Dose-Response Relationship, Drug ; Inhalation Exposure/adverse effects ; Inhalation Exposure/analysis ; Lethal Dose 50 ; Lung/drug effects ; Lung/pathology ; Male ; Phosgene/toxicity ; Pulmonary Edema/chemically induced ; Pulmonary Edema/pathology ; Rats, Wistar ; Survival Analysis ; Time Factors
Chemical Substances	Chemical Warfare Agents ; Phosgene (117K140075)
Language	English
Publishing date	2019-07-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2081252-8
ISSN	1537-6524 ; 1537-6516 ; 1051-7235
ISSN (online)	1537-6524
ISSN	1537-6516 ; 1051-7235
DOI	10.1080/15376516.2019.1636170
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Article ; Online: In vivo histone H1 migration from necrotic to viable tissue.

Luhrs, Keith A / Pink, Desmond / Schulte, Wendy / Zijlstra, Andries / Lewis, John D / Parseghian, Missag H

Oncotarget

2017 Volume 8, Issue 10, Page(s) 16275–16292

Abstract: Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1. ...

Abstract	Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1.2) was found to be transported from necrotic tumor cells into surrounding viable cells where histones are selectively taken up by energy-dependent endocytosis. We propose that intercellular histone trafficking could function as a target for drug delivery. This concept was validated using an anti-histone antibody that was co-internalized with histones from dead cells into viable ones surrounding the necrotic regions of a tumor, where some of the most chemoresistant cells reside. These findings demonstrate that cellular translocation of conjugated drugs using anti-histone antibodies is a promising strategy for targeted drug delivery to chemoresistant tumors.
MeSH term(s)	Animals ; CHO Cells ; Cell Line, Tumor ; Cell Survival ; Cricetinae ; Cricetulus ; Endocytosis ; Histones/metabolism ; Humans ; Necrosis ; Protein Transport
Chemical Substances	Histones
Language	English
Publishing date	2017-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.15181
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Article: Beyond the walls of the nucleus: the role of histones in cellular signaling and innate immunity.

Parseghian, Missag H / Luhrs, Keith A

Biochemistry and cell biology = Biochimie et biologie cellulaire

2006 Volume 84, Issue 4, Page(s) 589–604

Abstract: Although they are one of the oldest family of proteins known (first described in 1884 by Kossel), histones continue to surprise researchers with their ever expanding roles in biology. In the past 25 years, the view of core histone octamers as a simple ... ...

Abstract	Although they are one of the oldest family of proteins known (first described in 1884 by Kossel), histones continue to surprise researchers with their ever expanding roles in biology. In the past 25 years, the view of core histone octamers as a simple spool around which DNA in the nucleus is wound and linker histones as mere fasteners clipping it all together has transformed into the realization that histones play a vital role in transcriptional regulation. Through post-translational modifications, histones control the accessibility of transcription factors and a host of other proteins to multiple, conceivably thousands of, genes at once. While researchers have spent decades deciphering the role of histones in the overall structure of chromatin, it might surprise some to find that an entirely separate faction of scientists have focused on the role of histones beyond the confines of the nuclear envelope. In the past decade, there has been an accumulation of observations that suggest that histones can be found at the mitochondrion during the onset of apoptotic signaling and even at the cell surface, acting as a receptor for bacterial and viral proteins. More provocatively, immunologists are becoming convinced that they can also be found in the lumen of several tissues, acting as antimicrobial agents--critical components of an ancient innate immune system. Perhaps nowhere is this observation as dramatic as in the ability of neutrophils to entrap bacterial pathogens by casting out "nets" of DNA and histones that not only act as a physical barrier, but also display bactericidal activity. As our views regarding the role of histones inside and outside the cell evolve, some have begun to develop therapies that either utilize or target histones in the fight against cancer, microbial infection, and autoimmune disease. It is our goal here to begin the process of merging the dichotomous lives of histones both within and without the nuclear membrane.
MeSH term(s)	Animals ; Cell Nucleus/metabolism ; Histones/genetics ; Histones/metabolism ; Histones/physiology ; Humans ; Immunity, Innate/genetics ; Models, Biological ; Nuclear Envelope/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Signal Transduction
Chemical Substances	Histones ; Nuclear Proteins
Language	English
Publishing date	2006-08
Publishing country	Canada
Document type	Journal Article ; Review
ZDB-ID	54104-7
ISSN	0829-8211
ISSN	0829-8211
DOI	10.1139/o06-082
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Article ; Online: Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery.

Pink, Desmond B S / Schulte, Wendy / Parseghian, Missag H / Zijlstra, Andries / Lewis, John D

PloS one

2012 Volume 7, Issue 3, Page(s) e33760

Abstract: The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, ... ...

Abstract	The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.
MeSH term(s)	Animals ; Capillary Permeability/drug effects ; Cell Line ; Chick Embryo ; Chorioallantoic Membrane/blood supply ; Chorioallantoic Membrane/pathology ; Doxorubicin/administration & dosage ; Drug Delivery Systems ; Evans Blue ; Humans ; Interleukin-2/pharmacology ; Microscopy ; Neoplasms/blood supply ; Neoplasms/pathology ; Neovascularization, Pathologic ; Time-Lapse Imaging ; Transplantation, Heterologous/pathology ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A/pharmacology
Chemical Substances	Interleukin-2 ; Vascular Endothelial Growth Factor A ; Evans Blue (45PG892GO1) ; Doxorubicin (80168379AG)
Language	English
Publishing date	2012-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0033760
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Article ; Online: Evicting hitchhiker antigens from purified antibodies.

Luhrs, Keith A / Harris, Debra A / Summers, Scott / Parseghian, Missag H

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

2009 Volume 877, Issue 14-15, Page(s) 1543–1552

Abstract: Antibodies that target common cellular structures may have a propensity to bind those very same antigens as they become exposed in dead or dying cells during production in a bioreactor. Those tendencies can be accentuated if the targeted epitope is ... ...

Abstract	Antibodies that target common cellular structures may have a propensity to bind those very same antigens as they become exposed in dead or dying cells during production in a bioreactor. Those tendencies can be accentuated if the targeted epitope is highly conserved across species. While attention to contaminants such as endotoxin, viral particles, cellular DNA and even prions has grown coincident with the emergence of the monoclonal antibody industry, it is surprising how little attention has been focused on hitchhiker antigens that may co-elute while bound to the supposedly pure antibody. In this case study, we will focus on anti-histone antibodies and the measures we have taken to eliminate stowaways, such as histone-DNA complexes. These simple measures include the addition of a quartenary amine guard column to the protein A, adjusting the ionic strength of the cell culture supernatant to 400 mM sodium chloride, and establishing a mobile phase gradient from 400 mM to 2M during protein A chromatography. Initially adjusting the cell culture to 600 mM can compromise the quartenary amine guard column. Also, we demonstrate the applicability of these techniques in both the R&D lab and the manufacturing plant, particularly in improving the apparent potency of antibodies destined for the clinic. Given the prominence of anti-histone antibodies in chromatin immunoprecipitation (ChIP), the implications of hitchhiker antigens interferring with the results of an experiment are far-reaching, indeed, we detect them in some popularly used antibodies. Moreover, a wide variety of monoclonals that may target antigens expressed by the producer cell line may face similar problems, resulting in a decreased production yield, as well as a diminished apparent binding potency.
MeSH term(s)	Antibodies/immunology ; Antibodies/isolation & purification ; Antigens/immunology ; Chromatography, Affinity/methods ; DNA/immunology ; Histones/immunology ; Humans
Chemical Substances	Antibodies ; Antigens ; Histones ; DNA (9007-49-2)
Language	English
Publishing date	2009-05-15
Publishing country	Netherlands
Document type	Evaluation Studies ; Journal Article
ZDB-ID	1180823-8
ISSN	1873-376X ; 0378-4347 ; 1570-0232 ; 1387-2273
ISSN (online)	1873-376X
ISSN	0378-4347 ; 1570-0232 ; 1387-2273
DOI	10.1016/j.jchromb.2009.03.042
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Article ; Online: Real-time visualization and quantitation of vascular permeability in vivo

Desmond B S Pink / Wendy Schulte / Missag H Parseghian / Andries Zijlstra / John D Lewis

PLoS ONE, Vol 7, Iss 3, p e

implications for drug delivery.

2012 Volume 33760

Abstract	The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The effects of hitchhiker antigens co-eluting with affinity-purified research antibodies.

Mechetner, Lilly / Sood, Radhika / Nguyen, Van / Gagnon, Pete / Parseghian, Missag H

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

2011 Volume 879, Issue 25, Page(s) 2583–2594

Abstract: The popularity of Protein G for the purification of antibodies has given rise to an entire industry that supplies scientists with research grade immunoreagents; however, many times the supplied product is contaminated with antigens bound to the antibody' ... ...

Abstract	The popularity of Protein G for the purification of antibodies has given rise to an entire industry that supplies scientists with research grade immunoreagents; however, many times the supplied product is contaminated with antigens bound to the antibody's complementarity-determining regions (CDRs). These "hitchhikers" are a category of host cell proteins that are elusive to detect due to their interaction with the antibody in the final product and yet their impact on an experiment or an entire field of study can be far reaching. In an earlier work, the role of hitchhikers on a human anti-histone antibody destined for clinical usage was explored and a stringent purification scheme developed. Here we use a murine monoclonal, which reflects the type of commercial antibody usually purchased for research. We evaluate three purification schemes: a traditional approach using a one-step, low pH elution buffer (pH 2.5); a gentler approach using a pH gradient elution scheme (pH 7 down to pH 2.5); and finally, a more stringent purification patterned on our earlier published method that uses a quaternary amine guard column and a high salt wash during antibody immobilization on the Protein G. We stress that the stringent purification incorporates the pH gradient scheme and is gentler than the low-pH approach. The resulting product from all three purifications is directly compared for binding potency, histone content (using an ELISA based assay) and residual DNA (using quantitative PCR). The results demonstrate that the first two methods are inadequate for hitchhiker removal. The traditional one-step, low pH approach produces a single elution peak containing histone contaminated antibody with picogram quantities of residual DNA, however, the trailing end of the same peak is loaded with antibody complexed to nanogram amounts of DNA, in some cases, over 100 ng. The pH gradient approach provided antibodies accompanied by only picograms of residual DNA and, on average, 1 out of every 10-20 CDRs occupied by a histone antigen. The more stringent approach, using the salt wash prior to elution with the pH gradient, has an average of 1 out of every 75 CDRs contaminated with a histone while the majority of the residual DNA is captured by the quaternary amine column placed in front of the Protein G. The consequences of these contaminants is illustrated by showing how they manifest themselves in unusual antibody potency values ranging from 558% for antibody bound to histone hitchhikers down to 15% for antibody contaminated with DNA hitchhikers. Those samples purified by the recommended stringent approach show potency values between 90 and 101%. Most importantly, we repeatedly demonstrate in a simulated chromatin immunoprecipitation (ChIP) assay the ability to precipitate clean plasmid DNA with histone contaminated antibody that had been purified using the traditional one-step, low pH elution approach. Expectedly, those antibodies stringently purified and showing 100% binding potency were unable to precipitate DNA in the absence of histone hitchhikers.
MeSH term(s)	Animals ; Antibodies/chemistry ; Antibodies/isolation & purification ; Antigens/chemistry ; Bacterial Proteins ; Chromatin Immunoprecipitation ; Chromatography, Affinity/methods ; Complementarity Determining Regions ; DNA/isolation & purification ; Drug Contamination ; Goats ; Histones/isolation & purification ; Humans ; Hydrogen-Ion Concentration ; Immunoassay/standards ; Mice ; Quaternary Ammonium Compounds ; Rabbits
Chemical Substances	Antibodies ; Antigens ; Bacterial Proteins ; Complementarity Determining Regions ; Histones ; IgG Fc-binding protein, Streptococcus ; Quaternary Ammonium Compounds ; DNA (9007-49-2)
Language	English
Publishing date	2011-09-01
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	1180823-8
ISSN	1873-376X ; 0378-4347 ; 1570-0232 ; 1387-2273
ISSN (online)	1873-376X
ISSN	0378-4347 ; 1570-0232 ; 1387-2273
DOI	10.1016/j.jchromb.2011.07.016
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Article ; Online: High efficacy vasopermeability drug candidates identified by screening in an ex ovo chorioallantoic membrane model.

Pink, Desmond / Luhrs, Keith A / Zhou, Longen / Schulte, Wendy / Chase, Jennifer / Frosch, Christian / Haberl, Udo / Nguyen, Van / Roy, Aparna I / Lewis, John D / Zijlstra, Andries / Parseghian, Missag H

Scientific reports

2015 Volume 5, Page(s) 15756

Abstract: The use of rodent models to evaluate efficacy during testing is accompanied by significant economic and regulatory hurdles which compound the costs of screening for promising drug candidates. Vasopermeation Enhancement Agents (VEAs) are a new class of ... ...

Abstract	The use of rodent models to evaluate efficacy during testing is accompanied by significant economic and regulatory hurdles which compound the costs of screening for promising drug candidates. Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to increase the uptake of cancer therapeutics at the tumor site by modifying vascular permeability in the tumor to increase the therapeutic index of co-administered drugs. To evaluate the efficacy of a panel of VEA clinical candidates, we compared the rodent Miles assay to an equivalent assay in the ex ovo chicken embryo model. Both model systems identified the same candidate (PVL 10) as the most active promoter of vasopermeation in non-tumor tissues. An ex ovo chicken embryo system was utilized to test each candidate VEA in two human tumor models at a range of concentrations. Vasopermeation activity due to VEA was dependent on tumor type, with HEp3 tumors displaying higher levels of vasopermeation than MDA-MB-435. One candidate (PVL 10) proved optimal for HEp3 tumors and another (PVL 2) for MDA-MB-435. The use of the ex ovo chicken embryo model provides a rapid and less costly alternative to the use of rodent models for preclinical screening of drug candidates.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Capillary Permeability ; Cell Line, Tumor ; Chick Embryo ; Chorioallantoic Membrane/metabolism ; Drug Screening Assays, Antitumor/methods ; Humans ; Mice
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2015-10-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep15756
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