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Open Access Research article

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

Renate RJ de Groot-Besseling12*, Theo JM Ruers2, Iris L Lamers-Elemans3, Cathy N Maass1, Robert MW de Waal1 and Johan R Westphal12

Author Affiliations

1 Departments of Pathology, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

2 Department of Surgery, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

3 Central Animal Facility, University of Nijmegen, Geert Grooteplein 29, 6525 EZ Nijmegen, The Netherlands

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BMC Cancer 2006, 6:149  doi:10.1186/1471-2407-6-149

Published: 5 June 2006

Abstract

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.