Plasminogen mediates liver regeneration and angiogenesis after experimental partial hepatectomy.

BACKGROUND: Plasmin system components are upregulated after partial hepatectomy, but their contribution to surgery-induced hepatic angiogenesis and regeneration is unclear. Liver regeneration and angiogenesis after partial hepatectomy were examined in mice lacking plasminogen or urokinase plasminogen activator (uPA). METHODS: Mice with a single-gene deletion of plasminogen or uPA were subjected to 70 per cent partial hepatectomy. Liver regeneration was measured as relative liver weight and cell proliferation index. Angiogenesis was quantified by determining hepatic microvessel density after staining for sinusoidal endothelial cells. RESULTS: The liver remnant weight was significantly reduced in mice lacking plasminogen or uPA compared with that in wild-type mice on days 2 and 7 after partial hepatectomy. This correlated with impaired cell proliferation. In wild-type mice, regeneration was accompanied by a significant increase in microvessel density after hepatectomy; this increase was impaired in plasminogen-deficient mice. CONCLUSION: Plasminogen and uPA are essential for optimal liver regeneration. In addition, plasminogen appears to be a major determinant in regeneration-associated hepatic angiogenesis.

Angiostatin prolongs the survival of mice with leptomeningeal metastases.

BACKGROUND: As a result of the more effective treatment of primary tumours, the incidence of leptomeningeal metastases (LM) is increasing. Current treatment modalities have little effect on the survival of patients with LM. We investigated whether antiangiogenic treatment inhibits the progression of leptomeningeal tumours. MATERIALS AND METHODS: To assess the role of angiogenesis in leptomeningeal tumours, we inoculated melanoma cells in the subarachnoid space in balb/c mice. At different stages, the mice were sacrificed and the microvessel density was determined. Human specimens of LM were compared with the mouse model. For the intervention studies, the mice were treated with the angiogenesis inhibitor angiostatin. Survival was the endpoint in these studies. RESULTS: Tumour seeding in the early disease stages was concentrated around the pre-existent arachnoid vasculature. In the more advanced stages, the tumour masses covered larger areas of the leptomeninges. Arachnoidal microvessel density in this advanced stage was increased compared with control mice. Systemic treatment of the mice with LM with angiostatin (100 mg kg-1 day-1) resulted in prolonged survival compared with mice treated with vehicle and with approximately one-fifth of the long-term survivors of the angiostatin-treated group. CONCLUSIONS: This study shows that neovascularization is important in the growth of LM in mice. Systemic targeting of the vascular compartment may be a useful approach in novel therapeutic strategies for patients with LM.

Angiostatin inhibits pathological but not physiological retinal angiogenesis.

PURPOSE: Antiangiogenic treatment is a promising new therapy for angiogenesis-dependent diseases. In the current study, the biologic effects on pathologic and physiological angiogenesis in the retina of angiostatin, a very potent angiogenesis inhibitor were determined. In addition, the effects of angiostatin on the growth and development of newborn mice were examined. METHODS: Oxygen-induced retinopathy was induced by subjecting mice postnatal day (P)7 to hyperoxic conditions (5 days) followed by normoxic conditions (relative hypoxia). Mice were treated with angiostatin (intravitreal or systemic). Retinal blood vessels were visualized by fluorescein angiography. Retinal neovascularization was assessed by counting intravitreal endothelial cell nuclei. Growth and organogenesis were determined between P0 and P14. RESULTS: Relative hypoxia resulted in intravitreal proliferation of retinal blood vessels. However, proliferation was inhibited completely by systemic administration of angiostatin without affecting normal retinal vascularization. After intravitreal injection of angiostatin, pathologic proliferation of the retinal blood vessels was impaired by 62%. Neither systemic nor intravitreal treatment impaired the development or growth of organs throughout the body. CONCLUSIONS: Angiostatin inhibits oxygen-induced intravitreal pathologic retinal angiogenesis without affecting the development of physiological retinal vascularization, development, and growth of newborn mice. Therefore, antiangiogenic treatment may be a useful tool in the treatment of proliferative retinopathies.

Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy.

Human plasminogen-derived angiostatin is one of the most potent antiangiogenic agents currently known. However, it is unclear whether angiostatin is also effective against accelerated tumor growth induced by local up-regulation of growth factors, including angiogenesis stimulators, such as in regenerating liver. Prior to addressing this question, we tested, in mice, whether continuous administration of angiostatin could improve its biological effects. This assumption was based on the relatively short half-life of angiostatin in mice, as well as on the theoretical necessity to suppress tumor-induced angiogenesis continually. The findings presented here clearly indicate continuous administration to be superior to the conventional twice-daily bolus injections. Using the maximally effective regimen of 100 mg/kg/day via s.c. pump infusion, we found angiostatin to not only suppress s.c. primary tumors but also to significantly inhibit the outgrowth of colorectal hepatic metastases in resting liver and even to inhibit accelerated tumor growth in regenerating liver after 70% partial hepatectomy. In conclusion, angiostatin could play an important role in patients subjected to partial hepatectomy to prevent outgrowth of residual micrometastases, provided it is administered continuously to obtain maximal biological effects.

Implant failure four years after resection and reconstruction of a femur for a chondrosarcoma.

The authors describe an original reconstruction technique following resection for a chondrosarcoma of the femur. Although fatigue failure of the implant occurred four years later, they still think that this surgical procedure may be considered as a good treatment option in patients with a limited life expectancy.