Abstract
BackgroundUpregulation 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.MethodsIn 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.ResultsSurprisingly, 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.ConclusionOur 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.
Highlights
Upregulation of endogenous angiostatin levels may constitute a novel antiangiogenic, and anti-tumor therapy
As angiostatin is present in the circulation of healthy individuals [11]; Westphal, manuscript in preparation], boosting the angiostatin generating capacities of the host might provide an alternative for exogenous angiostatin administration
Angiostatin generation in vitro The optimal concentrations for in vitro angiostatin formation were investigated by incubating murine serum with uPA, type plasminogen activator (tPA), and/or a free sulfhydryl group donor, followed by western blot analysis of the reaction products
Summary
Upregulation of endogenous angiostatin levels may constitute a novel antiangiogenic, and anti-tumor therapy. 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. One class of anti-angiogenic compounds consists of proteolytic fragments of larger parent molecules Examples of this type of angiogenesis inhibitors are angiostatin and endostatin, that are fragments of plasminogen and collagen XVIII, respectively [6,7]. Administration of angiostatin – either alone, or in combination with radiotherapy or chemotherapy – resulted in potent inhibition of tumour growth and metastasis formation in several animal tumour models [14,14,15,16,17,18,19]. As angiostatin is present in the circulation of healthy individuals [11]; Westphal, manuscript in preparation], boosting the angiostatin generating capacities of the host might provide an alternative for exogenous angiostatin administration
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