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A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin

This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e.,...

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Autor principal: Parris, George E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674172/
https://www.ncbi.nlm.nih.gov/pubmed/26675544
http://dx.doi.org/10.2203/dose-response.14-020.Parris
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author Parris, George E.
author_facet Parris, George E.
author_sort Parris, George E.
collection PubMed
description This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor.
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spelling pubmed-46741722015-12-15 A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin Parris, George E. Dose Response Article This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor. SAGE Publications 2015-05-20 /pmc/articles/PMC4674172/ /pubmed/26675544 http://dx.doi.org/10.2203/dose-response.14-020.Parris Text en © The Author(s) 2015 http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm).
spellingShingle Article
Parris, George E.
A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title_full A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title_fullStr A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title_full_unstemmed A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title_short A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin
title_sort hypothesis concerning the biphasic dose-response of tumors to angiostatin and endostatin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674172/
https://www.ncbi.nlm.nih.gov/pubmed/26675544
http://dx.doi.org/10.2203/dose-response.14-020.Parris
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