Mechanism of action of angiostatic steroids: Suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis

Blei, Francine; El, Wilson; Mignatti, Paolo; Db, Rifkin

doi:10.1002/jcp.1041550315

Cited by 132 publications

(47 citation statements)

References 54 publications

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“…Therefore, inhibition of bFGF as well as VEGF by genistein may lead to prevention of metastasis. MPA is known to have an antiangiogenic effect via suppression of plasminogen activator activity (Blei et al, 1993). In our study, MPA did not induce a significant decrease in the level of either VEGF mRNA or bFGF mRNA in the concentrations employed.…”

Section: Discussioncontrasting

confidence: 45%

Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma

et al. 2002

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Since it has been widely recognised that renal cell carcinoma is refractory to standard therapies such as chemotherapy and radiotherapy, a new modality of treatment is needed. One of the potential alternative therapies for renal cell carcinoma may be inhibition of angiogenesis. In this study, we analysed the inhibitory effects of several potential agents on expression of angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor, which are the main mediators in angiogenesis of renal cell carcinoma. We used medroxyprogesterone acetate, interferon-alpha, interferon-gamma, minocycline hydrochrolide and genistein, which are known to be antiangiogeneic. Northern blot analyses revealed that, among the five agents examined, genistein had a strong inhibitory effect on expression of vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA. Medroxyprogesterone acetate and interferon-alpha did not significantly decrease the level of either vascular endothelial growth factor mRNA or basic fibroblast growth factor mRNA. Interferon-gamma and minocycline had mild inhibitory effects on vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA expression. Genistein also inhibited both vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA expression after treatment with epidermal growth factor and hypoxia. These findings suggest that one of the mechanisms of the inhibition of angiogenesis by genistein is suppression of the expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor in renal cell carcinoma.

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Section: Discussioncontrasting

confidence: 45%

Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma

et al. 2002

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“…In contrast, locally applied medroxyprogesterone has previously been shown to inhibit the angiogenesis induced by rabbit V2 carcinoma in rabbit cornea more potently than dexamethasone without heparin treatment (Gross et al, 1981). In the study of Blei et al (1993), the degree of PA inhibition by a variety of angiostatic steroids did not uniformly correlate with their efficacy obtained in the CAM assay (Crum et al, 1985). For example, dexamethasone and medroxyprogesterone were almost equipotent at inhibiting PA activity in cultured endothelial cells.…”

Section: Discussionmentioning

confidence: 92%

Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokine levels in rat sponge implants

Hori

Yasui

et al. 1996

British J Pharmacology

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1 Subcutaneous implantation of sterile polyether sponges elicited a reproducible neovascular response in rats, as determined by blood flow measurement with a 133Xe clearance technique and confirmed histologically. This model was used to monitor the levels of two cytokines during angiogenesis and to compare the activities of angiostatic steroids and anti-inflammatory steroids. 2 Initial experiments followed the neovascular development over a 20-day period. Daily local injection of hydrocortisone caused a dose-dependent (0.5, 5 and 50 Mg per sponge) inhibition of the basal spongeinduced angiogenesis. However, daily systemic treatment of hydrocortisone (2, 10 and 50 mg kg-', s.c.) was less effective at inhibiting angiogenesis, and this inhibition was not sustained by day 20 after sponge implantation. 3 To investigate the involvement of cytokines during the course of angiogenesis, we measured the endogenous levels of tumour necrosis factor-a (TNF-a) and interleukin 6 (IL-6) in sponge implants. Levels of IL-6 and TNF-a peaked at day 7 and day 11 after implantation, respectively. These cytokine levels subsided through the completion of angiogenesis by day 20. 4 Subsequent experiments were carried out over a 14-day period. Among the three angiostatic steroids tested, U-24067 (6a -fluoro -17,21 -dihydroxy -16a -methylpregna -4,9(11) -diene -3,20-dione -21-acetate) showed a dose-dependent inhibition (0.5, 5 and 50 ug per sponge per day) of sponge-induced angiogenesis. Tetrahydro-S was also effective at 5 Mg doses, but medroxyprogesterone failed to affect the angiogenic response. None of these steroids caused atrophies of the spleen and thymus. 5 Daily local injection of dexamethasone (0.5 Mg per sponge) inhibited the basal sponge-induced angiogenesis almost completely. Although higher doses of dexamethasone (5 and 50 Mg per sponge) did not produce further inhibition of angiogenesis, they caused severe spleen and thymus weight losses, indicative of immunosuppression.6 At the daily dose of 5 Mg per sponge, dexamethasone inhibited angiogenesis and produced a marked reduction in the levels of TNF-a and IL-6 at day 14. In contrast, hydrocortisone, U-24067 and tetrahydro-S did not influence the levels of TNF-a and IL-6. 7 We concluded that the anti-angiogenic activity of angiostatic steroids and anti-inflammatory steroids in the rat sponge model is independent of their ability to reduce the production of TNF-a and IL-6. The differential effects of angiostatic and anti-inflammatory steroids suggest that U-24067 and its derivatives may have therapeutic potential in the management of angiogenic diseases such as rheumatoid arthritis.

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“…But, at a higher concentration (25 nM), the morphology was similar to that in the case of Marimastat (data not shown). Since dexamethasone reportedly inhibits the production of PA 23) and MMP, 24) we checked the inhibitory activity of dexamethasone on PA production in our system. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Rat Aortic Fragment within Collagen Gel as an Angiogenesis Model; Capillary Morphology may Reflect the Action Mechanisms of Angiogenesis Inhibitors.

Hata-Sugi

Kawase-Kageyama

Wakabayashi

2002

Biological & Pharmaceutical Bulletin

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Angiogenesis, the formation of new blood vessels from pre-existing vessels, occurs physiologically during embryonal development, tissue injury and inflammation. It is also well known to play an important role in several pathological conditions, such as cancer, diabetic retinopathy, rheumatoid arthritis and atherosclerosis.1) An understanding of the angiogenic process may lead to new therapies for the above diseases, and some angiogenesis inhibitors are already under clinical study as anti-cancer drugs.2)The formation of new capillaries is a complex biological process whose regulatory mechanisms are incompletely understood. The initiation of angiogenesis involves focal reduction of intercellular interactions and of interactions between endothelial cells and the surrounding extracellular matrix (ECM). Cell migration, proliferation and capillary tube formation then follow. It is clear that complex orchestration of many processes, some overlapping, is required in order for angiogenesis to proceed. Various types of angiogenic growth factors such as vascular endothelial growth factor (VEGF), 3) basic fibroblast growth factor (bFGF), 4) platelet-derived growth factor (PDGF) 5) and hepatocyte growth factor (HGF) 6) stimulate both the endothelial cells and mesenchymal cells. ECM-degrading proteolytic enzymes, including matrix metalloprotease (MMP) and plasminogen activator (PA), are secreted by endothelial cells in response to angiogenic factors and/or cytokines. 7) Cell adhesion molecules such as integrins, cadherin and PECAM also regulate the angiogenic process.8) There are some reports on the interactions of the angiogenic factors mentioned above; for example, bFGF up-regulates VEGF production 9); the production of proteolytic enzymes and integrin alpha subunits is induced by VEGF, 10) bFGF 11) and PDGF 12); MMP-2 associates with integrin avb3 and growth factor receptor.13) Therefore, an in vitro model of angiogenesis should retain, as far as possible, the in vivo interactions of angiogenic factors and the regulatory mechanisms.Fragments of rat thoracic aorta within type I collagen gel provide a good model of the overall angiogenic process, including cell migration, proliferation and capillary tube formation, for 1 to 2 weeks. The aortic fragments contain several types of cells, such as endothelial cells, smooth muscle cells and fibroblasts, which co-ordinate to form capillary vessels in the collagen gel. It was reported that aortic fragments endogenously produce bFGF, 14) and exogenous growth factors such as PDGF, insulin-like growth fator (IGF) and VEGF enhance capillary formation. 15)In this report, we show that VEGF, its receptor and proteolytic enzymes (MMP, PA) are endogenously expressed in the rat aorta model and gradually increase during the process of angiogenesis. When the action of these endogenous factors was blocked by inhibitors, capillary tube formation was clearly inhibited, demonstrating that these endogenous factors play key roles in angiogenesis in this model. Interestingly, the formed capillaries a...

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Mechanism of action of angiostatic steroids: Suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis

Cited by 132 publications

References 54 publications

Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma

Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma

Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokine levels in rat sponge implants

Characterization of Rat Aortic Fragment within Collagen Gel as an Angiogenesis Model; Capillary Morphology may Reflect the Action Mechanisms of Angiogenesis Inhibitors.

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