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  At4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agentsUSPTO Application #: 20060128630Title: At4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agents Abstract: AT4 receptor agonists are potent activators of angiogenesis and can be used to treat diseases that are characterized by vascular insufficiency. AT4 receptor antagonists, which are potent inhibitors of angiogenesis, and can be used as anti-angiogenic agents for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerotic plaque formation, and any disease process that is characterized by excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells. (end of abstract)
Agent: Seed Intellectual Property Law Group PLLC - Seattle, WA, US Inventors: Joseph W. Harding, John W. Wright USPTO Applicaton #: 20060128630 - Class: 514016000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 7 Or 8 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060128630. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation of U.S. patent application Ser. No. 10/675,470, filed Sep. 30, 2003, now pending, which application is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to the general utility of AT.sub.4 receptor ligands to alter blood vessel growth (angiogenesis) in diseases associated with insufficient blood supply or those associated with excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells. In particular, AT.sub.4 receptor ligands that inhibit angiogenesis are extremely potent anti-cancer agents that block both the growth of primary tumors and the development of metastatic tumors. [0004] 2. Description of Related Art [0005] The dominant therapeutic approaches that are currently employed to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral application of anti-mitotic cytotoxic agents. The continued dominance of these long established therapies is mirrored by the lack of improvement in survival rates for most cancers. Improvements that have been observed can be traced not to therapeutic advancements but diagnostic ones. In addition to limited clinical success, devastating side effects accompany classic therapies. Both radiation- and cytotoxic-based therapies result in the destruction of rapidly dividing hematopoietic and intestinal epithelial cells leading to compromised immune function, anemia, and impaired nutrient absorption. Surgical intervention often results in a release of tumor cells into the circulation or lymph systems from which metastatic tumors can subsequently be established. Furthermore, primary tumors often produce or generate endogenous anti-angiogenic substances that suppress the growth of already established but undetected micrometastases (O'Reilly et al., 1994). Their removal, without accompanying treatment that is directed at the micrometastases often leads to rapid expansion of the metastatic tumors with fatal consequences. [0006] Because of the shortcomings of classic treatment regimens several new approaches to cancer therapy have been initiated over the past decade. Most prominent among these are the development of vaccines directed at cancer cells (Morris et al., 2003), the related use of immunotoxins (antibodies linked to cytotoxic agents) (Pastan and Kreitman, 2002), hormone-based therapies (Kenemans and Bosman, 2003), and anti-angiogenics that are designed to limit tumor growth and metastasis by inhibiting tumor vascularization (Kerbel and Folkman, 2002). Although, the vaccine and immunotoxin therapeutic approach has been under development for some time no immuno-based therapy is now in use as a standard cancer treatment. The utility of this approach is limited by two properties that are inherent to cancer cells. First, cancers are derived from many cell types all with different antigenic profiles. Therefore, each cancer type would necessarily require its own specific set of therapeutic reagents that would entail prohibitively expensive individual development. Second, the antigenic targets of the reagents would never be totally unique to the transformed cancer cells but would also be represented on normal healthy cells resulting in unwanted cytotoxic damage. Hormone-based therapies, while useful for the treatment of a select group of cancers, will never be a treatment option that is generally applicable to the vast majority of cancers that are hormone insensitive. The successful development of a new and generally useful cancer therapy must meet two critical criteria. First, the treatment must target a molecular target or process that is associated with most (if not all) cancers. Next, the treatment must have little or no impact on normal cells. Unlike immune- or hormone-based cancer therapies, anti-angiogenic-based therapies meet both of these criteria. [0007] Neovasularization of tumors is requisite for both the growth and metastasis of tumors. The vascularization of tumor provides it with a dedicated source of nutrients and oxygen that are essential for continued growth. Without a dedicated blood supply the availability of nutrients and oxygen, which must be furnished by vessels external to the neoplasm, is diffusion limited restricting tumor size to about 1 millimeter in diameter. In addition to providing nutrients and oxygen, the tumor vasculature, which is often abnormally permeable, acts as a conduit enabling cancer cells to escape into the general circulation from whence they can establish metastatic tumors at distant sites. The inverse relationship between tumor vascularization and patient prognosis is well recognized and reflects the fact that 90% of cancer patients die of metastatic disease and not primary tumors. The realization that most, if not all, tumors require a dedicated blood supply in order to progress to a clinically relevant state spawned the notion that inhibiting tumor neovasularization could control cancer progression. This could be accomplished by blocking the process of angiogenesis in which vascular endothelial cells divide and migrate to produce branching of established vessels. A particularly attractive aspect of targeting angiogenesis is that the frequency of cancer is increased in older adults who possess quiescent endothelial cells with a normal turnover rate of 1000 days and occurs only during wound healing and menses. Thus, anti-angiogenic drugs meet the primary criteria for a general anti-cancer agent- i.e., broad applicability and minimal effects on normal tissues. Another advantage offered by anti-angiogenic drugs is that they target a cell population (endothelial cells) that is genetically stable and far less likely to support the development of drug resistance that is regularly seen with drugs directed at cancer cells. A final advantage offered by anti-angiogenics is their ready access to endothelial target cells following parenteral application. BRIEF SUMMARY OF THE INVENTION [0008] A method of increasing angiogenesis in pathological conditions associated with insufficiencies in vascular perfusion, by producing an AT.sub.4 receptor agonist; and administering the AT.sub.4 receptor agonist. A method of inhibiting angiogenesis in pathological conditions, where increased angiogenesis and coincidental vascular perfusion are clinically detrimental, by producing an AT.sub.4 receptor antagonist; and administering the AT.sub.4 receptor antagonist. A method of inhibiting the growth and metastasis of solid tumors, by producing an AT.sub.4 receptor antagonist; and administering the AT.sub.4 receptor antagonist. A method of inhibiting the growth and metastasis of breast cancer, by producing an AT.sub.4 receptor antagonist; and administering the AT.sub.4 receptor antagonist. [0009] In any of the above methods the AT.sub.4 receptor ligand can be administered locally, intravascularly, intramuscularly, intraperitoneally, subcutaneously, or orally. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS [0010] FIGS. 1A and 1B shows the effect of the AT.sub.4 receptor agonist, Nle.sup.1-AngIV (NORLEU), and the AT.sub.4, receptor antagonist, Nle.sup.1, Leu.sup.3-.PSI.(CH.sub.2--NH.sub.2).sup.3-4-Ang IV (NORLEUAL), on the growth of human umbilical vein endothelial cells. [0011] FIG. 2 shows the effect of the AT.sub.4 receptor antagonist on the net deposition of extracellular matrix protein by human dermal fibroblasts and C6 glioma cells. [0012] FIG. 3 shows the effect of various AT.sub.4 receptor ligands on the expression and secretion of matrix metalloproteinases by rabbit cardiac fibroblasts. [0013] FIG. 4 shows the effect of the AT.sub.4 receptor antagonist, NORLEUAL, on the net deposition of extracellular matrix protein by human umbilical vein endothelial cells and +SA-WAZ-2T murine breast cancer cells. [0014] FIGS. 5A and 5B show the effect of the AT.sub.4 receptor antagonist, NORLEUAL, on the ex vivo development of new blood vessels in the rat aortic ring angiogenesis assay. [0015] FIGS. 6A and 6B show the effect of various AT.sub.4 receptor ligands on in vivo angiogenesis in the rat disc angiogenesis assay. [0016] FIG. 7 shows the inhibitory effect of the AT.sub.4 receptor antagonist, NORLEUAL, on the growth of +SA-WAZ-2T murine primary tumors in mice. [0017] FIGS. 8A and 8B shows the inhibition of tumor angiogenesis in mice following application of the AT.sub.4 receptor antagonist, NORLEUAL. [0018] FIG. 9 shows inhibition in the development of lung metastasis in mice following injection of +SA-WAZ-2T cells into the tail vein and subsequent application of the AT.sub.4 receptor antagonist, NORLEUAL. [0019] FIG. 10 shows the inhibition of MDA-MB-231 human breast cancer growth by the AT.sub.4 receptor antagonist, NORLEUAL. [0020] FIG. 11 shows the inhibition of human prostate cancer growth by an AT.sub.4 receptor antagonist. Continue reading... Full patent description for At4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this At4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agents patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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