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Results for “Angiogenesis Inhibitors”

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At least 19 recordsLinked to original sources
PubMed1990

Development of angiogenesis inhibitors for clinical applications.

Angiogenesis, the development of new blood vessels, is associated with many life-threatening pathologies. The neovascularization of tumors for example, allows a blood supply to deliver the required nutrients for tumor development. Inappropriate blood vessel growth also contributes to the pathology of other diseases such as atherosclerosis and arthritis. The process of angiogenesis is beginning to be better understood, and as Ted Maione and Richard Sharpe explain, this understanding has led to the identification of several lead compounds that inhibit this process. At present all of these candidate drugs exhibit severe host toxicity, but more selective angiogenesis inhibitors might be expected to be extremely useful therapeutic agents.

Animals↗
PubMed1992

Effect of 15-deoxyspergualin, a microbial angiogenesis inhibitor, on the biological activities of bovine vascular endothelial cells.

We found recently that 15-deoxyspergualin, an analog of spergualin, which is an antibiotic and includes a spermidine moiety in its structure, exhibits anti-angiogenic activity. We have now carried out in vitro experiments with bovine vascular endothelial cells to determine which events occurring during angiogenesis are affected by this microbial angiogenesis inhibitor. 15-Deoxyspergualin did not inhibit the production of urokinase-type plasminogen activator (u-PA) or type IV collagenase by vascular endothelial cells. The direct inhibition of u-PA activity by 15-deoxyspergualin was not observed either. The angiostatic antibiotic neither affected the migration of vascular endothelial cells nor inhibited the endothelial cell proliferation in a two-dimensional culture system. We also examined the effect of 15-deoxyspergualin on the proliferation of endothelial cells in a three-dimensional culture system involving collagen gel, in which cell growth resembles more closely the endothelial cell proliferation during in vivo angiogenesis than that in a two-dimensional culture system without collagen gel. The antibiotic inhibited cell proliferation in a dose-dependent manner, indicating that the three-dimensional culture system is useful for finding a new angiogenesis inhibitor with a different mode of action from those of angiogenesis inhibitors found by using a two-dimensional assay system; however, no cause-effect relationship has yet been established. Taken together, these results suggest the possible involvement of the inhibition of vascular endothelial cell growth by 15-deoxyspergualin in its angiogenesis-inhibitory effect. 15-Deoxyspergualin appears to be a promising candidate as an angiogenesis inhibitor for controlling aberrant angiogenic responses occurring in different states, including tumor development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Eponemycin, a novel antibiotic, is a highly powerful angiogenesis inhibitor.

Eponemycin, a novel antibiotic, was examined as to its anti-angiogenic activity in an in vivo assay system involving chorioallantoic membranes (CAMs) of growing chick embryos. Eponemycin powerfully inhibited angiogenesis in the CAMs. This powerful inhibition was dose-dependent, the inhibitory activity becoming detectable at a dose of 7.5 fmol/egg and the ID50 value being 250 fmol/egg, suggesting that eponemycin exhibits more potent anti-angiogenic activity than Ch 55, a synthetic retinoid, which had been the strongest angiogenesis inhibitor identified so far. To determine which event(s) in the angiogenesis process was affected by eponemycin, experiments were conducted using systems involving cultured vascular endothelial cells. Eponemycin effectively inhibited both the proliferation and migration of endothelial cells, indicating that the antibiotic affected these two important events during angiogenesis, resulting in effective inhibition of angiogenesis. These results strongly suggest that eponemycin could be a promising candidate as an angiogenesis inhibitor for the control of aberrant angiogenesis occurring in different diseases such as tumor development and diabetic retinopathy.

Allantois↗
PubMed1992

A new angiogenesis inhibitor, FR-111142.

FR-111142 is a new angiogenesis inhibitor produced by a fungus Scolecobasidium arenarium F-2015. FR-111142 inhibited endothelial cell proliferation in vitro and angiogenesis in the growing chick chorioallantoic membrane model in vivo. Further, FR-111142 also suppressed the solid tumor growth in mice.

Allantois↗
PubMed1992

Angiogenesis and angiogenesis inhibitors in paediatric diseases.

Angiogenesis, the generation of new capillaries from existing blood vessels, is rarely observed in the healthy organism, but can present during various paediatric diseases. In this review, we describe recent progress in the understanding of pathological angiogenesis and approaches for an improved therapy of angiogenic childhood diseases.

Angiogenesis Inducing Agents↗
PubMed1992

The angiogenesis inhibitor beta-cyclodextrin tetradecasulfate inhibits ecto-protein kinase activity.

The growth of new blood vessels plays an important role in the pathogenesis of several diseases including cancer, diabetes, and arthritis. Beta-cyclodextrin tetradecasulfate, when administered with an appropriate steroid inhibits angiogenesis, and can stimulate angiogenesis when given alone. The regulation of angiogenesis is not well understood, and the mechanism of action of beta-cyclodextrin tetradecasulfate is similarly not well defined. Ecto-protein kinase activity that utilizes extracellular ATP has recently been reported on several types of cells. Human neutrophils appear to possess two distinct ecto-protein kinase activities; one that phosphorylates exogenous substrates including vitronectin and basic fibroblast growth factor, and one that phosphorylates endogenous cell-surface proteins. This report shows that beta-cyclodextrin tetradecasulfate inhibits the phosphorylation of the exogenous substrates casein, vitronectin (the major ecto-protein kinase substrate in serum), and basic fibroblast growth factor by human neutrophil ecto-protein kinase activity. In contrast, beta-cyclodextrin tetradecasulfate had no effect on the phosphorylation of endogenous cell-surface proteins by the neutrophil ecto-protein kinase activity. Ecto-protein kinase activity that was inhibited by beta-cyclodextrin tetradecasulfate was also detected on porcine aortic and human umbilical vein endothelial cells. The effects of beta-cyclodextrin tetradecasulfate on ecto-protein kinase activities may play a role in its effects on angiogenesis.

Caseins↗
PubMed1991

Antitumor effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3, a potent angiogenesis inhibitor, on rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene.

The effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1,25(OH)2D3) on the growth of autochthonous rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) was examined on the basis of our previous finding that this synthetic vitamin D3 analog has a potent angiogenesis inhibitory effect. Two doses of 22-oxa-1,25(OH)2D3, 0.1 and 1 microgram/kg of body weight, due to the limited amount of the compound available, were used. The daily administration of 22-oxa-1,25(OH)2D3 at the dose of 1 microgram/kg/day resulted in significant inhibition of the growth of these mammary tumors at 1, 2 and 3 weeks after the administration of this agent, although the agent caused little or no regression of the tumors. After daily administration for 3 weeks, a significant antitumor effect was also observed in the group treated with 0.1 microgram/kg/day. Treatment with 22-oxa-1,25(OH)2D3 did not affect the serum calcium levels in the treated rats. The lower dose of 22-oxa-1,25(OH)2D3 neither affected weight gain nor caused a decrease in body weight, while the higher dose, although having some effect on weight gain, did not induce a decrease in body weight. There were no significant differences in the weights of adrenals, uteri and ovaries between the treated groups and controls. These results suggest that 22-oxa-1,25(OH)2D3 has a significant growth inhibitory effect on DMBA-induced autochthonous mammary tumors in rats, without producing severe side effects, including hypercalcemic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Inhibitors of angiogenesis.

Angiogenesis, the formation of new capillaries, is essential to a number of important physiological events, both normal and pathological. Recently, increased attention has focused on the purification and characterization of inhibitors of this process, because of the potential therapeutic value of angiogenesis inhibitors in controlling such "angiogenic diseases" as proliferative retinopathy, solid tumors, rheumatoid arthritis, and neovascular glaucoma. We review the process of neovascularization and the assays that have been developed to study its inhibition in vivo and in vitro. We also discuss the properties of different angiogenesis inhibitors and examine the mechanisms by which such inhibitors could potentially intervene in the process of neovascularization.

Animals↗
PubMed1990

A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin.

A secreted inhibitor of angiogenesis that is controlled by a tumor suppressor gene in hamster cells has been found to be similar to a fragment of the platelet and matrix protein thrombospondin. The two proteins were biochemically similar and immunologically crossreactive and could substitute for one another in two functional assays. Human thrombospondin inhibited neovascularization in vivo and endothelial cell migration in vitro, as does the hamster protein, gp140. gp140 sensitized smooth muscle cells to stimulation by epidermal growth factor, as does human thrombospondin. The thrombospondin gene has been localized on human chromosome 15. These results demonstrate a function for the ubiquitous adhesive glycoprotein thrombospondin that is likely to be important in the normal physiological down-regulation of neovascularization. In addition, they raise the possibility that thrombospondin may be one of a number of target molecules through which a tumor suppressor gene could act to restrain tumor growth.

Amino Acid Sequence↗
PubMed1990

Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.

Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.

Animals↗
PubMed1992

[Emoxipin as an inhibitor of angiogenesis].

The effect of emoxypin on angiogenesis in rabbit cornea in aseptic inflammation induced by intracorneal implantation of a piece of quartz and on the development of the vessels of the chick embryo yolk sac was studied. 1% emoxypin pipetted thrice a day for 10-14 days inhibited corneal neovascularization and reduced the formation of new blood vessels. We observed an inhibitory effect on the development of vascular bed of the embryo yolk sac on incubation hour 64-72. The drug affected neither general growth of the embryos no the number of somites.

Animals↗
PubMed1991

Extracellular matrix and cell shape: potential control points for inhibition of angiogenesis.

Capillary endothelial (CE) cells require two extracellular signals in order to switch from quiescence to growth and back to differentiation during angiogenesis: soluble angiogenic factors and insoluble extracellular matrix (ECM) molecules. Soluble endothelial mitogens, such as basic fibroblast growth factor (FGF), act over large distances to trigger capillary growth, whereas ECM molecules act locally to modulate cell responsiveness to these soluble cues. Recent studies reveal that ECM molecules regulate CE cell growth and differentiation by modulating cell shape and by activating intracellular chemical signaling pathways inside the cell. Recognition of the importance of ECM and cell shape during capillary morphogenesis has led to the identification of a series of new angiogenesis inhibitors. Elucidation of the molecular mechanism of capillary regulation may result in development of even more potent angiogenesis modulators in the future.

Animals↗
PubMed1992

Selective endothelial growth inhibition by tetracyclines that inhibit collagenase.

The potential of angiogenesis inhibitors as therapy for human diseases is limited by a lack of clinically available agents. We investigated the mechanism of the anti-angiogenesis effects of minocycline, a commonly used drug, and several derivatives. Endothelial cell proliferation was inhibited by several of these compounds. We found that inhibition was associated with inhibition of collagenase, did not require antibiotic activity, and was not related to cytotoxicity. Other microvessel-associated cells were unaffected. This endothelial antiproliferative effect is a potential mechanism of the anti-angiogenic activity of minocycline.

Animals↗
PubMed1990

Suppression of tumor-forming ability and related traits in MCF-7 human breast cancer cells by fusion with immortal mammary epithelial cells.

Somatic cell hybrids between MCF-7 human breast cancer cells and normal immortalized human mammary epithelial cells have been obtained by polyethylene glycol-mediated cell fusion. The hybrid cells are suppressed in their ability to form tumors in nude mice, as well as in traits specific to the tumorigenic MCF-7 parent: growth factor independence, tumor necrosis factor sensitivity, and pS2 gene expression. In addition, they display other characteristics of the "normal" parent, including increased expression relative to the MCF-7 cells of the genes for the extracellular matrix component fibronectin, the intermediate filament keratin 5, and the angiogenesis inhibitor thrombospondin. The levels of keratins 8 and 18 also resemble those of the nontumorigenic parent. These results provide evidence for the existence of tumor suppressor gene products in immortal mammary epithelial cells. We propose a characteristic "suppressed" tumor cell phenotype, which encompasses altered cytoarchitecture, angiogenesis capabilities, and growth factor requirements.

Animals↗