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Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators

BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises an...

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Autores principales: de Groot-Besseling, Renate RJ, Ruers, Theo JM, Lamers-Elemans, Iris L, Maass, Cathy N, de Waal, Robert MW, Westphal, Johan R
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560151/
https://www.ncbi.nlm.nih.gov/pubmed/16753063
http://dx.doi.org/10.1186/1471-2407-6-149
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author de Groot-Besseling, Renate RJ
Ruers, Theo JM
Lamers-Elemans, Iris L
Maass, Cathy N
de Waal, Robert MW
Westphal, Johan R
author_facet de Groot-Besseling, Renate RJ
Ruers, Theo JM
Lamers-Elemans, Iris L
Maass, Cathy N
de Waal, Robert MW
Westphal, Johan R
author_sort de Groot-Besseling, Renate RJ
collection PubMed
description BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models. METHODS: In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model. RESULTS: Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril. CONCLUSION: Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy.
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spelling pubmed-15601512006-09-06 Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators de Groot-Besseling, Renate RJ Ruers, Theo JM Lamers-Elemans, Iris L Maass, Cathy N de Waal, Robert MW Westphal, Johan R BMC Cancer Research Article BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models. METHODS: In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model. RESULTS: Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril. CONCLUSION: Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy. BioMed Central 2006-06-05 /pmc/articles/PMC1560151/ /pubmed/16753063 http://dx.doi.org/10.1186/1471-2407-6-149 Text en Copyright © 2006 de Groot-Besseling et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
de Groot-Besseling, Renate RJ
Ruers, Theo JM
Lamers-Elemans, Iris L
Maass, Cathy N
de Waal, Robert MW
Westphal, Johan R
Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title_full Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title_fullStr Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title_full_unstemmed Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title_short Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators
title_sort angiostatin generating capacity and anti-tumour effects of d-penicillamine and plasminogen activators
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560151/
https://www.ncbi.nlm.nih.gov/pubmed/16753063
http://dx.doi.org/10.1186/1471-2407-6-149
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