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 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

Comparison of in situ and remotely-sensed (SeaWiFS) chlorophyll-a in the Northwest Atlantic

341-355Field measurements of phytoplankton pigment (chlorophyll-a) from the Northwest Atlantic are compared with concurrent pigment concentrations derived from SeaWiFS data using NASA/SeaDAS algorithms known as Ocean Chlorophyll 2 (OC2) and OC4 (versions 4.1 and 4.3). The results showed broad agreement but estimates using the NASA algorithms tended to show uncertainties, with lower than in situ values at concentrations greater than 1 mg chl-a m⁻³. Regionally -, and seasonally-, adapted empirical corrections are developed in an attempt to reduce the bias. The magnitude of errors was quantified using linear regression. Further progress will require application of a theoretical regional ocean-colour model