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  Vanadium compounds as anti-angiogenic agentsUSPTO Application #: 20060183729Title: Vanadium compounds as anti-angiogenic agents Abstract: Vanadium compounds for inhibiting angiogenesis useful for treating or preventing diabetic retinopathy, hemangiomas, cancers with abnormal blood vessel supply, restenosis following vascular injury, and the like. (end of abstract)
Agent: Merchant & Gould PC - Minneapolis, MN, US Inventor: Fatih M. Uckun USPTO Applicaton #: 20060183729 - Class: 514184000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Heavy Metal Containing (including Salts) The Patent Description & Claims data below is from USPTO Patent Application 20060183729. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a divisional application of U.S. patent application Ser. No. 09/713,780, filed on Nov. 15, 2000, which application is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Tissue growth is intimately associated with blood supply. Non-vascularized tissue is limited in size, often being smaller than one to two millimeters in diameter or thickness. Therefore, inhibiting blood supply to tissue represents one target point for limiting tissue growth and possibly tissue viability. [0003] The ability to inhibit blood supply has been shown to play a pivotal role in the progression, invasive and metastatic growth of malignant tumors (Folman, Nat Med, 1:27, 1995; Folkman et al, Science, 235:442, 1985; Gimbrane et al, J Exp Med, 136:261, 1972). Further, inhibition of angiogenesis new vessel formation), has been shown to result in tumor dormancy or regression and to prevent metastasis (Folkman, Ann Surg, 175:409, 1972; Taylar et al, Nature, 297:307, 1982). [0004] Another possible target for inhibiting tissue growth is by inhibiting cell proliferation. All proliferating eucaryotic cells must undergo mitosis before separating into two new cells. Mitosis is a process in which the parent or replicating cell undergoes a series of molecular events that results in the formation of two nuclei in the place of one. [0005] The polar mitotic spindle is critical to the separation of the replicated chromosomes and formation of the two nuclei in the mitotic process. For mitosis to proceed normally, cells must properly form a bipolar mitotic spindle with bivalent chromosomes properly attached to each pole of the spindle (Gorbsky et al, Bioessays, 19: 193-197, 1997; Hardwick, K. G., Trends Genet., 14: 1-4, 1998). Cells which do not form a correct mitotic spindle arrest indefinitely in the metaphase stage of mitosis or progress into apoptosis. Several proteins identified in yeast and mammals have been implicated in this process, including MAD1 (mitotic arrest deficient), MAD2, and MAD3 (Li et al, Cell, 66: 519-531, 1991 (published erratum appears in Cell, 79(2), following p388)), BUB1 (budding uninhibited by benzimidazole), BUB2 and BUB3 (Hoyt et al, Cell, 66: 507-517, 1991). Mammalian counterparts for these proteins include HsMAD2 (Li et al, Supra and hBUB1 (Cahill et al, Nature, 392: 300-303, 1998). [0006] Revascularization of obstructed coronary arteries by percutaneous transluminal coronary angioplasty (PTCA) has become an integral component of front-line treatment programs for patients with ischemic heart disease (Vaitkus, P. T., 1995, Coron. Atery Dis., 6:429-439). Although acute complications of PTCA have markedly declined with optimized use of anticoagulants, antispasmodic agents, and intravascular stents, the incidence of coronary artery restenosis has remained at 30%-50% and represents the major obstacle to a more successful outcome of PTCA (Landzberg, et. al., 1997, Prog. Cardiovascular Diseases, 39:361-298). Therefore, the development of effective strategies for restenosis prophylaxis has become a focal point for translational cardiovascular research. [0007] The pathogenesis of restenosis has been compared to an exaggerated wound healing response with migration of smooth muscle cells from the media to the intima of the revascularized coronary artery where they proliferate and cause an obstructive neointimal hyperplasia (Ueda et al., 1995, Coron. Artery Dis., 6:71-81). Many factors contribute to the development of restenosis, including vascular injury, platelet aggregation, procedural factors, inflammation, and mitogenic stimulation of migration and proliferation of smooth muscle cells. The relative contribution of any one of these factors remains unclear. [0008] Pharmacological approaches to prevent restenosis include antiplatelet and antithrombotic agents, anti-inflammatory drugs, growth factor antagonists, vasodilators, antiproliferatives, antineoplastics, photochemotherapy, and lipid lowering agents. Some growth factor antagonists have also been studied for effects on restenosis. [0009] Inhibition of vascular smooth muscle cell proliferation by a platelet derived growth factor (PDGF)-antagonist has generated promising results in preclinical as well as early clinical studies, thereby confirming the biologic importance of vascular smooth muscle cells in the pathophysiology of restenosis (Mullins et al., 1994, Arterioscler. Thromb., 14:1047-1055). [0010] Considerable efforts are underway to develop new anti-angiogenic and anti-mitotic agents for use as therapies in the treatment of tumor growth and spread. Accordingly, there is a need for the analysis of novel, effective anti-angiogenic and anti-mitotic agents that target tumor growth. [0011] Vanadocene dichloride (VDC) has been shown to arrest tumor cells growth (Kopf-Maier, et al, J Cancer Res. Clin. Onccol., 106: 44-52, 1983). The oxovanadium compound, VO(Phen)(H.sub.2O)2](SO.sub.4), has been shown to be an active agent against pharyngonasal cancer as determined by a single assay (Sakurai, et. al, BBRC, 206: 133, 1995). Vanadium compounds, including vanadocenes, have also been demonstrated to induce apoptosis in cancer cells (Uckun et al., WO 00/35930). [0012] Against this backdrop the present invention has been developed. SUMMARY OF THE INVENTION [0013] It has been now found that vanadium compounds, for example vanadocenes and oxovanadium compounds, are poent agents for inhibiting angiogenesis. In particular, the vanadium compounds have been found to exhibit dual function inhibiting both angiogenesis and mitosis. Pharmaceutical compositions containing these vanadium compounds are thus useful in methods to inhibit angiogenesis and mitosis, for example, in the treatment diabetic retinopathy, hemangiomas, cancers with abnormal blood vessel supply, restenosis following vascular injury, and the like. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0014] The present invention relates to vanadium compounds, including, for example, vanadium cyclopentadienyl complexes (vanadocenes), such as vandocene acetylacetonate (VDacac) and oxovanadium compounds, and the finding that these vanadium compounds have potent anti-angiogenic and anti-mitotic activities. [0015] Vanadium is a physiologically essential element that can be found in both anionic and cationic forms with oxidation states ranging from -3 to +5 (I-V). This versatility provides unique properties to vanadium complexes. In particular, the catonic form of vanadium complexes having an oxidation state of +4 (IV) has been shown to function as a modulator of cellular redox potential, regulate enzymatic phosphorylation, and exert pleiotropic effects in multiple biological systems by catalyzing the generation of reactive oxygen species (ROS). Besides the ability of vanadium metal to assume various oxidation states, its coordination chemistry also plays a key role in its interactions with various biomolecules. In particular, it is demonstrated herein that vanadium compounds, such as vanadium cyclopentadienyl complexes, oxovanadium complexes, or derivatives thereof, exhibit anti-angiogenic and anti-mitotic properties. Definitions [0016] The following terms and phrases as used herein have the noted definitions, unless otherwise described: [0017] "Halo" is fluoro, chloro, bromo, or iodo. "Alkyl", "alkoxy", etc. denote both straight and branched hydrocarbon groups; but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" is specifically referenced. [0018] "Organometallic compound" is an organic compound comprised of a metal attached directly to carbon (R-M). [0019] "Coordination compound" is a compound formed by the union of a central metal atom or ion with ions or molecules called ligands or complexing agents. Continue reading... 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