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At least 19 recordsLinked to original sources
PubMed2000

Clinical strategy for the development of angiogenesis inhibitors.

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.

Angiogenesis Inhibitors↗
PubMed2002

Clinical translation of angiogenesis inhibitors.

Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?

Angiogenesis Inhibitors↗
PubMed2005

[Research advancement of endogenous angiogenesis inhibitors].

Angiogenesis is required for invasive tumor growth and metastasis. Inhibition of angiogenesis is considered to be a promising approach of antitumor therapy. Recently, many endogenous angiogenesis inhibitors have been discovered, some of them are currently in various stages of clinical trials. This review focused on the structure, function, and mechanism of endogenous angiogenesis inhibitors, and their potential in treating tumor.

Angiogenesis Inhibitors↗
PubMed2000

Angiogenesis inhibitors.

Angiogenesis inhibitors target the neovascular development that is hypothesized to underlie tumor growth. The inhibitors that are undergoing the clinical testing phase can be divided into five categories based on their target activity: 1) drugs that block matrix breakdown; 2) drugs that inhibit endothelial cells directly; 3) drugs that block angiogenesis activators; 4) drugs that inhibit endothelial cell integrins or survival signaling; and 5) drugs with a currently unknown mechanism of action. The properties of these drugs and some specific agents in each class are reviewed in this article. Because growth inhibition rather than tumor shrinkage is expected to be the clinical effect of angiogenesis inhibitors, some of the challenges and potential solutions for clinical trial design are also discussed.

Angiogenesis Inhibitors↗
PubMed1998

Natural products as angiogenesis inhibitors.

Angiogenesis is a strictly controlled process in the healthy, adult human body. It is regulated by a variety of endogenous angiogenic and angiostatic factors. It is only switched on, e.g., during wound healing. Pathological angiogenesis occurs, for example, in cancer, chronic inflammation, or atherosclerosis. Angiogenesis inhibitors are able to interfere with various steps of angiogenesis, like basement destruction of blood vessels, proliferation and migration of endothelial cells, or the lumen formation. Among the known angiogenesis inhibitors compounds derived from natural sources, like flavonoids, sulphated carbohydrates, or triterpenoids are playing a prominent role.

Adult↗
PubMed1997

The preclinical evaluation of angiogenesis inhibitors.

Angiogenesis is a fundamental process which is required for a number of physiological and pathophysiological processes. The field of angiogenesis therefore has many therapeutic implications and has progressed rapidly. Many strategies have been devised to regulate angiogenesis and several endogenous and synthetic inhibitors of angiogenesis have now been identified. These inhibitors can be used to treat a number of angiogenesis-dependent diseases and they offer a novel means of potently inhibiting tumor growth without significant toxicity or drug resistance. Recently, some of these inhibitors have entered clinical trials. In this article, I will review methods currently employed in the preclinical evaluation of angiogenesis inhibitors and I will discuss some of the implications of angiogenesis research.

Allantois↗
PubMed2002

Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor.

Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.

Angiogenesis Inhibitors↗
PubMedDate not supplied

SU6668, a multitargeted angiogenesis inhibitor.

Angiogenesis plays a critical role in the growth and metastasis of solid and hematologic malignancies. This complex and highly regulated process involves numerous different cell types and mediators. Vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor are among the soluble factors that stimulate this process. They are ligands for specific tyrosine kinase receptors that are important in transduction of intracellular signals and induction of angiogenesis. SU6668 is a novel molecule that competitively inhibits the tyrosine kinase of the receptors for vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, and c-kit. In vitro studies have confirmed that SU6668 inhibits growth factor-stimulated tyrosine phosphorylation. SU6668 also has significant antitumor activity against many types of tumor xenograft explants in athymic mice. SU6668 inhibits angiogenesis through several mechanisms, including the induction of apoptosis in vascular endothelial cells and tumor cells. Currently, Phase 1 studies are being initiated to evaluate the potential of SU6668 as an anticancer agent for humans.

Angiogenesis Inhibitors↗
PubMed2003

Heparin derivatives as angiogenesis inhibitors.

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumor neovascularization and in angioproliferative diseases. Tumors cannot growth as a mass above few mm(3) unless a new blood supply is induced. It derives that the control of the neovascularization process may affect tumor growth and may represent a novel approach to tumor therapy. Angiogenesis is controlled by a balance between proangiogenic and antiangiogenic factors. The angiogenic switch represents the net result of the activity of angiogenic stimulators and inhibitors, suggesting that counteracting even a single major angiogenic factor could shift the balance towards inhibition. Heparan sulfate proteoglycans are involved in the modulation of the neovascularization that takes place in different physiological and pathological conditions. This modulation occurs through the interaction with angiogenic growth factors or with negative regulators of angiogenesis. Thus, the study of the biochemical bases of this interaction may help to design glycosaminoglycan analogs endowed with angiostatic properties. The purpose of this review is to provide an overview of the structure/function of heparan sulfate proteoglycans in endothelial cells and to summarize the angiostatic properties of synthetic heparin-like compounds, chemically modified heparins, and biotechnological heparins.

Angiogenesis Inducing Agents↗
PubMed1980

Control of tumor growth in animals by infusion of an angiogenesis inhibitor.

Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were < 3% of those in control animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weight < 2.5% of implants in mice receiving Ringer's solution, Trasylol, or albumin. Histologic study of major organs and standard blood tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.

Animals↗
PubMed1999

Mechanisms of tumor angiogenesis and therapeutic implications: angiogenesis inhibitors.

Angiogenesis is the development of new blood vessels from the existing vascular bed. In normal conditions this tightly regulated process occurs only during embryonic development, the female reproductive cycle and wound repair. In contrast, in pathological conditions such as malignant growth, atherosclerosis and diabetic retinopathy, angiogenesis becomes persistent due to an imbalance in the interplay between the positive and negative regulatory signals controlling the process. Thus, the control of tumor neovascularization may lead to new therapeutic approaches. Indeed, several anti-angiogenic drugs are currently undergoing preclinical characterization and/or clinical investigation. Recent achievement has clarified the mechanisms of action leading to pathological angiogenesis and has highlighted the role of hypoxia, growth factors, growth factor-receptors, enzymes and cell adhesion molecules involved in the process. This knowledge has permitted the design of receptor antagonists, adhesion molecule blockers and new targeted vascular approaches including gene therapy.

Animals↗
PubMed2002

Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis.

The brain-specific angiogenesis inhibitor 1 gene has been isolated in an attempt to find fragments with p53 "functional" binding sites. As reported herein and by others, brain-specific angiogenesis inhibitor 1 expression is present in some normal tissues, but is reduced or lost in tumour tissues. Such data and its particular structure prompted the hypothesis that brain-specific angiogenesis inhibitor 1 may act as a mediator in the local angiogenesis balance. We herein demonstrate that brain-specific angiogenesis inhibitor 1 over-expression suppresses tumour angiogenesis, delaying significantly the human tumour growth in immunodeficient mice. The inhibitory effect of brain-specific angiogenesis inhibitor 1 was documented using our intravital microscopy system, strongly implicating brain-specific angiogenesis inhibitor 1 as a mediator in the control of tumour angiogenesis. In contrast, in vitro tumour cell proliferation was not inhibited by brain-specific angiogenesis inhibitor 1 transfection, whereas some level of cytotoxicity was assessed for endothelial cells. Immunohistochemical analysis of tumour samples confirmed a reduction in the microvessel density index in brain-specific angiogenesis inhibitor 1-overexpressing tumours. At messenger level, moderate changes could be detected, involving the down-regulation of vascular endothelial growth factor and collagenase-1 expression. Furthermore, brain-specific angiogenesis inhibitor 1 expression that was lost in a selection of human cancer cell lines could be restored by wild-type p53 adenoviral transfection. Brain-specific angiogenesis inhibitor 1 should be considered for gene therapy and development of efficient drugs based on endogenous antiangiogenic molecules.

Adenocarcinoma↗
PubMed1999

[Advances in the study of mechanisms of the tumor angiogenesis inhibitors].

Tumor angiogenesis inhibitor is the drugs which can destroy or inhibit neovascularization, and block the growth and metastasis of cancer. For clinical applications it may be useful to divide the antiangiogenic drugs into two categories: class 1(specific inhibitors) and class 2 (non-specific inhibitors). This review intends to provide the recent progress of the mechanisms of antiangiogenic drugs (1) Regulation of angiogenesis growth factors; (2) Inhibition of basement membrane degradation; (3) Mediating signal transduction pathway; (4) Effect of cell cycle; (5) Regulation of tumor-related gene.

Angiogenesis Inhibitors↗
PubMed2002

The X-ray crystallographic structure of the angiogenesis inhibitor angiostatin.

Angiogenesis inhibitors have gained much public attention recently as anti-cancer agents and several are currently in clinical trials, including angiostatin (Phase I, Thomas Jefferson University Hospital, Philadelphia, PA). We report here the bowl-shaped structure of angiostatin kringles 1-3, the first multi-kringle structure to be determined. All three kringle lysine-binding sites contain a bound bicine molecule of crystallization while the former of kringle 2 and kringle 3 are cofacial. Moreover, the separation of the kringle 2 and kringle 3 lysiner binding sites is sufficient to accommodate the alpha-helix of the 30 residue peptide VEK-30 found in the kringle 2/VEK-30 complex. Together the three kringles produce a central cavity suggestive of a unique domain where they may function in concert.

Amino Acid Sequence↗
PubMedDate not supplied

Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.

BACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth.

Allantois↗
PubMed2003

Sphingosine 1-phosphate and cell migration: resistance to angiogenesis inhibitors.

Naturally occurring angiogenesis inhibitors can inhibit different steps of the angiogenic process, such as endothelial cell migration. However, the mechanisms underlying this inhibition have not been elucidated. We demonstrate that migration of human umbilical vein endothelial cells induced by the potent endothelial cell chemoattractant sphingosine 1-phosphate is refractory to inhibition by well-characterized angiogenesis inhibitors such as endostatin and plasminogen-related protein-B. Our data support the contention that for effective blockage of tumor-induced angiogenesis, antagonists of both G protein-coupled receptor signaling and receptor tyrosine kinase signaling must be combined.

Angiogenesis Inhibitors↗
PubMed2004

Perillyl alcohol is an angiogenesis inhibitor.

Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Thus, antiangiogenic therapy is one of the most promising approaches to control cancer. In the present work, we examined the ability of perillyl alcohol (POH), a dietary monoterpene with well-established tumor chemopreventive and chemotherapeutic activity, to interfere with the process of angiogenesis. POH remarkably prevented new blood vessel growth in the in vivo chicken embryo chorioallantoic membrane assay and proved to be effective in inhibiting the morphogenic differentiation of cultured endothelial cells into capillary-like networks both in collagen gel and Matrigel models. In addition, POH reduced the cell number in a proliferation assay and induced apoptosis of endothelial cells as indicated by the POH-mediated increase of caspase-3 activity and DNA fragmentation. Consistent with the observed antisurvival effect, POH treatment resulted in a significant inhibition of Akt phosphorylation in endothelial cells. Finally, POH was able to differentially modulate the release of two important angiogenic regulators: vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2). POH decreased the release of VEGF from cancer cells but stimulated the expression of Ang2 by endothelial cells, indicating that it might suppress neovascularization and induce vessel regression. Overall, these data underscore the antiangiogenic potential of POH and suggest that POH, in addition to its anticancer activity, may be an effective agent in the treatment of angiogenesis-dependent diseases.

Angiogenesis Inhibitors↗
PubMed2005

Dobesilate is an angiogenesis inhibitor.

Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Antiangiogenic therapy is one of the most promising approaches to treat such diseases. Dobesilate is an oral agent for treatment of vascular complications of diabetic retinopathy. We have examined the possibility that this compound could interfere with the process of angiogenesis in a mouse gelatine sponge assay using acidic fibroblast growth factor (aFGF) as an inducer of neovascularization. According to the results reported here, dobesilate remarkably reduced vessel ingrowth in aFGF-containing subcutaneous sponges in mice. These findings suggest that dobesilate could be an effective agent in the treatment of angiogenesis-dependent diseases involving FGFs.

Angiogenesis Inhibitors↗