Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-01-05
2002-04-30
Pryor, Alton (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06380253
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the use of anti-angiogenic agents in the cure of cell proliferative disorders including cancer and other disorders caused by uncontrolled angiogenic activity in the body. More particularly, the invention is directed to the efficacious use of anti-angiogenic agents.
BACKGROUND OF THE INVENTION
The term angiogenesis refers to the generation or formation of new blood vessels into a tissue or organ. Angiogenesis can occur both during some physiological processes and/or in some pathological conditions. For example, angiogenesis can be seen to occur during wound healing, fetal growth, corpus luteum, and endometrium, etc., (1). Endothelial cells, which cause to form the inner lining of the blood vessels, are constituted by a thin layer of epithelial cells and these cells are necessary for the process of angiogenesis. During the process of angiogenesis, irrespective of whether it is physiological or pathological, the endothelial cells release enzymes which can produce erosions of the basement membrane through which the endothelial cells cause protrusions. In response to the stimuli given by various agents, endothelial cells proliferate and migrate through the protrusions and form a sprout of the parent blood vessel. These endothelial cell sprouts can merge to form capillary loops leading to the formation of new blood vessel(s). If the blood vessels are in a tumor area, these new blood vessels in turn will provide enough nutrients and energy sources so that tumor cells can divide, proliferate and grow both in number and size. Thus, the process of angiogenesis is both essential and critical to the growth of cancer. The other pathological states in which angiogenesis plays a critical role include: rheumatoid arthritis, psoriasis, scleroderma, myocardial angiogenesis, corneal diseases, diabetic retinopathy associated with neovascularization, macular degeneration, ovulation, menstruation etc. The process of angiogenesis also appears to be critical for tumor metastasis.
Since angiogenesis is such a critical process in the promotion of cancer and tumor metastasis, several researches have been trying to devise methods or develop drugs which can selectively suppress angiogenesis with the hope that this would eventually lead to the inhibition of tumor growth. There are other situations where uncontrolled angiogenesis is undesirable. For instance, formation of new blood vessels in an area like cornea during the process of healing of the corneal ulcer, if it is in excess, can lead to corneal scar formation.
In the case of rheumatoid arthritis, angiogenesis can lead to continued inflammation in the joints and also to osteoporosis. In such an instance, prevention of formation of new blood vessels will lead to reduction in inflammation and also prevention of fibrous ankylosis and bony ankylosis. Thus, selective prevention and control of angiogenesis may be of benefit in the aforementioned conditions, as well as in several other conditions such as: uterine fibroids, psoriasis, scleroderma, diabetic retinopathy, keloids, ovulation etc. Another area where prevention of angiogenesis will be of benefit is in the inhibition of ovulation and menstruation and growth of placenta and this will lead to prevention of fertilization and growth of the fetal tissue. This may, thus, form a new approach in the development of fertility control measures.
Two naturally occurring molecules which have been identified to adversely influence or inhibit angiogenesis are angiostatin® and endostatin® (2). Both these molecules are proteins. Angiostatin® is a protein of molecular weight approximately 38 kD and has an amino acid sequence substantially similar to that of a fragment of murine plasminogen beginning at amino acid number 98 of an intact murine plasminogen molecule. The amino acid sequence of angiostatin® varies only slightly between species. The amino acid sequence of the human angiostatin® is substantially similar to the murine plasminogen fragment. But, it may be mentioned here that the active human angiostatin® sequence starts either at the amino acid number 97 or 99 of an intact human plasminogen amino acid sequence. In addition, human plasminogen has potent anti-angiogenic activity even in a mouse tumor model. This explains why both murine and human plasminogens and angiostatin®/endostatin® molecules show fairly similar anti-angiogenic activities in a variety of animal tumor models (3).
U.S. Pat. No. 5,792,845 issued on Aug. 11, 1998 to O'Reilly et al teaches that therapies directed at control of the angiogenic process could lead to the abrogation or mitigation of certain diseases. O'Reilly et al suggests that modulation of the formation of capillaries in angiogenic processes (such as wound healing and reproduction) is useful since undesired and uncontrolled angiogenesis can cause certain diseases to progress. O'Reilly et al teaches that angiostatin® protein has the capability of inhibiting angiogenesis, eg., to inhibit the growth of bovine capillary endothelial cells in culture in the presence of fibroblast growth factor.
U.S. Pat. No. 5,932,545 issued on Aug. 3, 1999 to Henkin et al teaches an anti-angiogenic drug in the form of a peptide or a salt thereof, to treat cancer, arthritis and retinopathy. The Henkin et al patent states however that angiogenesis inhibitors could cause systemic toxicity in humans.
Angiostatin® in the O'Reilly patent '845 is described and claimed as an Isolated nucleotide molecule with a specific sequence. It has been stated however that the angiostatin® molecule as known at present is not suitable for clinical trials.
Endostatin®, which is also similar to angiostatin®, has been shown to cause a dramatic reduction of primary and metastatic tumors in experimental animals. Endostatin® is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin® could specifically inhibit endothelial cell proliferation and angio-genisis and thus, block tumor growth (2, 4).
It is important to note that angiostatin® is derived from plasminogen or plasmin. It has been shown that human prostate carcinoma cell lines express enzymatic activity that can generate bioactive angiostatin® from purified human plasminogen or plasmin This bioactive angiostatin® has been shown to inhibit human endothelial cell proliferation, basic fibroblast growth factor-induced migration, endothelial cell tube formation, and basic fibroblast growth factor-induced corneal angiogenesis. In an extension of this study, it was noted that a serine proteinase is necessary for angiostatin® generation (5).
Angiostatin®, derived from plasminogen, selectively inhibits endothelial cell proliferation. When angiostatin® is given systemically it shows potent inhibitory action on the growth of tumor and renders metastatic and primary tumors to go into a dormant state by striking a balance between the rate of proliferation and apoptosis of the tumor cells (6). The very identification of angiostatin® has come from the observation that when a primary tumor is present, the growth of metastases is suppressed. On the other hand, after tumor removal, the previously dormant metastases develop new blood vessels (neovascularization) and grow. Both serum and urine from the tumor-bearing animals, but not from controls, showed very specific inhibitory action on the growth of endothelial cells. Subsequent studies led to the purification of this inhibitor of endothelial cells which was later identified as a 38 kD plasminogen fragment namely angiostatin®. It is now known that angiostatin®, which can also be obtained by a limited proteolytic digestion of human plasminogen, but not intact plasminogen can be administered systemically to block neovascularization and growth of metastases and primary tumors. A recombinant human angiostatin® which comprises of kringles 1-4 of human plasminogen (amino acids 93-470) expressed in
Pichia pastoris
has been prepared and is now available for use. This recombinant angiostatin® showed the same physical properties as that of the natural a
EFA Sciences LLC
Nath Rama B
Pryor Alton
LandOfFree
Method of stabilizing and potentiating the action of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of stabilizing and potentiating the action of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of stabilizing and potentiating the action of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2917006