| Combinatorial chemotherapeutic efficacy in non-Hodgkin lymphoma can be predicted by a signaling model of CD20 pharmacodynamics. | |
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MedLine Citation:
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PMID: 22350416 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Combination chemotherapy represents the standard-of-care for non-Hodgkin lymphoma. However, the development of new therapeutic regimens is empirical and this approach cannot be used prospectively to identify novel or optimal drug combinations. Quantitative system pharmacodynamic models could promote the discovery and development of combination regimens based upon first principles. In this study, we developed a mathematical model that integrates temporal patterns of drug exposure, receptor occupancy, and signal transduction to predict the effects of the CD20 agonist rituximab in combination with rhApo2L/TNF-related apoptosis inducing ligand or fenretinide, a cytotoxic retinoid, upon growth kinetics in non-Hodgkin lymphoma xenografts. The model recapitulated major regulatory mechanisms, including target-mediated disposition of rituximab, modulation of proapoptotic intracellular signaling induced by CD20 occupancy, and the relative efficacy of death receptor isoforms. The multiscale model coupled tumor responses to individual anticancer agents with their mechanisms of action in vivo, and the changes in Bcl-xL and Fas induced by CD20 occupancy were linked to explain the synergy of these drugs. Tumor growth profiles predicted by the model agreed with cell and xenograft data, capturing the apparent pharmacologic synergy of these agents with fidelity. Together, our findings provide a mechanism-based platform for exploring new regimens with CD20 agonists. |
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Authors:
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John M Harrold; Robert M Straubinger; Donald E Mager |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-02-20 |
Journal Detail:
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Title: Cancer research Volume: 72 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-04-04 Completed Date: 2012-05-24 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1632-41 Citation Subset: IM |
Copyright Information:
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©2012 AACR. |
Affiliation:
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Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal, Murine-Derived / administration & dosage, pharmacokinetics, pharmacology Antigens, CD20 / analysis, physiology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use* Cell Proliferation / drug effects Fenretinide / administration & dosage, pharmacokinetics Humans Lymphoma, Non-Hodgkin / drug therapy* Mice Models, Biological Signal Transduction* TNF-Related Apoptosis-Inducing Ligand / administration & dosage, pharmacokinetics Tissue Distribution |
| Grant Support | |
ID/Acronym/Agency:
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GM57980/GM/NIGMS NIH HHS; R01 GM057980/GM/NIGMS NIH HHS; R01 GM057980-14/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal, Murine-Derived; 0/Antigens, CD20; 0/TNF-Related Apoptosis-Inducing Ligand; 0/rituximab; 65646-68-6/Fenretinide |
| Comments/Corrections | |
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