Antiangiogenic activity

Systematic screening experiments have identified more than 100 synthetic compounds with potent antiangiogenic activity. The mode of action for most of these molecules is not well understood, but some of the 40 compounds are well advanced in clinical trials (Table 3). The first substance to have entered clinical trials was the Fumagillin-derivative AGM 1470. Fumagillin is an antibiotic which inhibits bFGF- and PDGF-induced endothelial cell proliferation. The mechanism of action of AGM 1470 is poorly understood, but it was shown that it binds and inhibits the metalloprotease methionine aminopeptidase (MetAp-2). 

The C-terminal NCI domain, called type XV endostatin or restin, has antiangiogenic activity similar to endostatin, the NCI domain of type XVIII collagen (see below). ° ° The NCI domain has a trimerization domain, a hinge region that is more sensitive to proteolysis in type XVIII collagen, and the endostatin domain. Lack of type XV collagen in mice causes a skeletal myopathy and cardiovascular defects. ... 

Jung M, Tak J, Chung WY, Park KK. (2006) Antiangiogenic activity of deoxoartemisinin derivatives on chorioallantoic membrane. Bioorg Med Chem Lett 16 1227-1230. 

J. J. (2006) CRA-026440 a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo. Molecular Cancer Therapeutics, 5, 1693-1701. 

Abstract Angiogenesis, the recruitment of new blood vessels, is a crucial mechanism required for both tumor growth and metastasis. Advances in the understanding of the molecular mechanisms underlying the angiogenesis process have led to the discovery of a variety of pharmaceutical agents with antiangiogenic activity. The potential... 

Antiangiogenic activity as a heparanase inhibitor, HCII-mediated anticoagulant Preclinical studies inhibitor of tumor metastasis, tumor growth, and angiogenesis 38, 39... 

The flavonoids fisetin and genistein exhibit antiangiogenic activity as evaluated in in vivo studies [279]. Flavonoids may also exert a limiting effect on tumor metastasis by way of their inhibitory activity on proteolytic enzymes such as trypsin, leucine aminopeptidase and other... 

Fortier AH, Nelson BJ, Grella DK, Holaday JW. Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst 1999 91 1635-1640. 

Tasquinimod (structure shown in Fig. 4) is a second-generation orally active quinoline-3-carboxamide analog with enhanced potency against prostate cancer via its antiangiogenic activity. It is presently undergoing clinical trials [35]. Androgen ablation and taxanes are standard therapies for metastatic prostate cancer [36]. 

Linomide (A/-phenylmethyl-l,2-dihydro-4-hydroxyl-l-methyl-2-oxo-qui-noline-3-carboxamide, structure given in Table 1) has been proven to be an immunomodulator [32], In clinical trials, it has been shown to be a potential treatment for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis and multiple sclerosis [37-39]. It has also been reported to possess antiangiogenic activity [33,40]. 

Like tasquinimod, linomide yields robust and consistent in vivo growth inhibition of prostate cancer models due to its antiangiogenic activity, and it inhibits of autoimmune encephalomyelitis models of multiple sclerosis (MS). MS clinical trials were discontinued because of unacceptable toxicity, due to dose-dependent induction of proinflammation [35]. 

Shi et al. reported on the synthesis and antiangiogenic activities of lino-mide and its analogs (compounds 11-16) [32], Three of the analogs are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the chicken chorioallantoic membrane (CAM) [41,42] angiogenesis assay. These compounds possessed considerable antiproliferative activities against isolated human umbilical vein endothelial (HUVEC) cells along with with no... 

MS-based mass profiling combined with multivariate analysis identified platelet factor 4, a chemokine with prothrombolytic and antiangiogenic activities, as a diagnostically predictive protein in depleted serum of prostate cancer patients [99]. SELDI-TOF-MS was applied to the discovery of serum markers of bone metastasis in prostate cancer. Unique isoforms of serum amyloid A were identified in these patients. Machine-learning algorithms were used to identify these patients with a sensitivity and specificity of 89% [100],... 

VFL is a novel vinca alkaloid obtained by semisynthesis using super-acidic chemistry to introduce two fluorine atoms selectively at the 20 position of VRLB. The preclinical evaluations of the new derivative VFL have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identifled properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semisynthetic vinca alkaloids. VFL is presently in phase III experimentation for treatment of bladder cancer and nonsmall-cell lung cancer (NSCLC) [72]. 

Cortistatins A-D (10-13) were isolated from the marine sponge Corticium simplex [13]. These steroidal alkaloids are unrelated to cortistatin, a neuropeptide stmcturally related to the hormone somatostatin which has antiangiogenic activity [14]. 

Marzola, P., Degrassei, A., Calderan, L., etal. (2004) In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model. Clinical Cancer Research, 10, 739—750. 

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