| Autor: |
de Groot-Besseling, Renate RJ, Ruers, Theo JM, Lamers-Elemans, Iris L, Maass, Cathy N, de Waal, Robert MW, Westphal, Johan R |
| Předmět: |
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| Zdroj: |
BMC Cancer; 2006, Vol. 6, p149-10, 10p, 6 Graphs |
| Abstrakt: |
Background: Upregulation of endogenous angiostatin levels may constitute a novel antiangiogenic, 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 Dpenicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/Dpenicillamine 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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