Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-11-09
2002-11-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C536S013200
Reexamination Certificate
active
06482802
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention is directed to a method for treating subjects having an angiogenesis-related disease by administering neomycin or an analogue thereof. The present invention is also directed to a pharmaceutical composition comprising (a) neomycin or an analogue thereof, and, optionally, (b) another anti-angiogenic agent or an anti-cancer agent. The invention is further directed to a method for screening neomycin analogues having anti-angiogenic activity. In a preferred embodiment, neomycin is administered to subjects having angiogenesis-related diseases. In other embodiments, neomycin or an analogue thereof is administered with another anti-angiogenic agent. In additional embodiments, neomycin or an analogue thereof is administered with an anti-neoplastic agent to treat subjects having an angiogenesis-related disease which is a cancer.
2. BACKGROUND OF THE INVENTION
2.1. Angiogensis
Angiogenesis is the complex process of blood vessel formation. The process involves both biochemical and cellular events, including (1) activation of endothelial cells (ECs) by an angiogenic stimulus; (2) degradation of the extracellular matrix, invasion of the activated ECs into the surrounding tissues, and migration toward the source of the angiogenic stimulus; (3) proliferation and differentiation of ECs to form new blood vessels (See, e.g., Folkman et al., 1991, J. Biol. Chem. 267:10931-10934).
The control of angiogenesis is a highly regulated process involving angiogenic stimulators and inhibitors. In healthy humans and animals, angiogenesis occurs under specific, restricted situations. For example, angiogenesis is normally observed in fetal and embryonal development, development and growth of normal tissues and organs, wound healing, and the formation of the corpus luteum, endometrium and placenta.
2.2. Angiogenesis-Related Diseases
The control of angiogenesis is altered in certain diseases. Many such diseases involve pathological angiogenesis (i.e., inappropriate, excessive or undesired blood vessel formation), which supports the disease state and, in many instances, contributes to the cellular and tissue damage associated with such diseases. Angiogenesis-related diseases (i.e., those involving pathological angiogenesis) are myriad and varied. They include, but are not limited to, various forms of tumors, chronic inflammatory diseases, and neovascularization diseases.
The formation and metastasis of tumors involve pathological angiogenesis. Like healthy tissues, tumors require blood vessels in order to provide nutrients and oxygen and remove cellular wastes. Thus, pathological angiogenesis is critical to the growth and expansion of tumors. Tumors in which angiogenesis is important include solid tumors as well as benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas.
Pathological angiogenesis also plays an important role in tumor metastasis. Pathological angiogenesis is important in two aspects. In one, the formation of blood vessels in tumors allows tumor cells to enter the blood stream and to circulate throughout the body. In the other, angiogenesis supports the formation and growth of new tumors seeded by tumor cells that have left the primary site.
Pathological angiogenesis is also associated with certain blood-borne tumors such as leukemias, and various acute or chronic neoplastic diseases of the bone marrow. It is believed that pathological angiogenesis plays a role in the bone marrow abnormalities that give rise to such leukemia-like tumors.
Pathological angiogenesis also plays a prominent role in various chronic inflammatory diseases such as inflammatory bowel diseases, psoriasis, sarcoidosis and rheumatoid arthritis. The chronic inflammation that occurs in such diseases depends on continuous formation of capillary sprouts in the diseased tissue to maintain an influx of inflammatory cells. The influx and presence of the inflammatory cells produce granulomas and thus, maintains the chronic inflammatory state.
For a general discussion of the role of angiogenesis in angiogenesis-related diseases see the following references: Moses et al., 1991, BioTechol. 9:630-633; Leek et al., 1994, J. Leuko. Biol. 56:423-435; and Beck et al., 1997, FASEB J. 11:365-373.
2.3. Angiogenic Factors and their Actions
Both normal and pathological angiogenesis apparently require action by one or more angiogenic factors. Many such factors have been identified. They include angiogenin (ANG), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), tumor necrosis factor-alpha (TNF-&agr;), tumor growth factor-alpha (TGF-&agr;), and tumor growth factor-beta (TGF-&bgr;).
There has not been a complete elucidation of the mechanism(s) by which angiogenic factors induce the various biochemical and cellular events of angiogenesis. However, much is known regarding the action of angiogenin in inducing angiogenesis, which may at least partially model the angiogenic action of other angiogenic factors.
Angiogenin was first isolated from tumor-conditioned culture medium as a result of a search for tumor angiogenic factors (Fett et al., 1985, Biochemistry 24:5480-5486). This search was based on the hypothesis that tumors will not grow beyond a minuscule size unless they are supplied with new blood vessels to provide nutrients and facilitate gas exchange (Folkman, J., 1971, N. Engl. J. Med. 285:1182-1186). Tumors elicit the formation of new blood vessels by secreting angiogenesis factors. Angiogenin has been shown to be a potent inducer of angiogenesis (Hu et al., 1998, in
Human Cytokines, Handbook for Basic and Clinical Research,
Vol. III, ed. Aggarwal, B. B. pp. 67-91, Blackwell Sciences, Inc., Maldan, Mass.). It induces the formation of new blood vessels in the chorioallantoic membrane (CAM) of chick embryos, and in the cornea and meniscus of the knee of rabbits (Fett et al., 1985, Biochemistry 24:5480-5486, King et al., 1991, J. Bone Joint Surg. 73-B: 587-590).
Angiogenin normally circulates in human plasma at a concentration of about 250 to 360 ng/ml (Blaser et al., 1993, Eur. J. Clin. Chem. Clin. Biochem. 31: 513-516, Shimoyama et al., 1996, Cancer Res. 56:2703-2706). Plasma angiogenin may promote wound healing when it becomes extravascular, e.g., through trauma. Angiogenin mRNA and protein are elevated in tissues and cells of patients with a variety of tumors (Chopra et al., 1995, Proc. Ann. Meet. Am. Assoc. Cancer Res. 36:A516; Li et al., 1994, J. Path. 172:171-175; and Moroianu et al., 1994, Proc. Natl. Acad Sci. USA 91:1677-1681).
Structure/function studies have shown that angiogenin has a weak but characteristic ribonucleolytic activity (Shapiro et al., 1986, Biochemistry 25:3527-35328). That activity appears to be essential for its angiogenic activity (Shapiro et al., 1989, Biochemistry 28:1726-17329). Compounds that inhibit angiogenin's ribonucleolytic activity also inhibits its angiogenic activity. Many such compounds have been identified or developed. They include the C-terminal peptides of angiogenin (Rybak et al., 1989, Biochem. Biophys. Res. Comm. 162:535-543), the ribonuclease inhibitor from human placenta (Lee et al., 1988, Biochemistry 27:8545-8553, Shapiro et al., 1987, Proc. Natl. Acad Sci. USA 84:2238-2241) and, more recently, a deoxynucleotide aptamer obtained by exponential enrichment.
Angiogenin apparently must interact with endothelial cells in order to induce angiogenesis. Several such interactions have been identified. Angiogenin binds to actin (Hu et al., 1991, Proc. Natl. Acad. Sci. USA 88:2227-2231, Hu et al., 1993, Proc. Natl. Acad Sci. USA 90:1217-1221) and to a 170 kDa putative receptor (Hu et al., 1997, Proc. Natl. Acad. Sci. USA 94:2204-2209) which are expressed on the surface of endothelial cells growing in dense and sparse culture, respectively. Binding of angiogenin to endothelial cells results in activation of phospholipase C (PLC) (Bicknell et al., 1988, Proc. Natl. Acad Sci. USA 85:5961-5965), endothelial cell migration
Hu Guo-fu
Vallee Bert L.
Endowment for Research in Human Biology, Inc.
Pennie & Edmonds LLP
Raymond Richard L.
LandOfFree
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