Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1996-11-15
1999-11-23
Caputa, Anthony C.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
530417, 530828, C07K 14435, C07K 14515
Patent
active
059902809
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to an angiogenesis inhibiting factor. More particularly, the factor (GD-AIF" hereafter), is induced in the presence of wild type p53, but not in the presence of any of the mutant forms of p53 which have been tested. The factor has an apparent molecular weight in its active form of approximately 100 kd and is labile to base and acid.
BACKGROUND AND PRIOR ART
Angiogenesis, the sprouting of new capillaries from small venules, occurs through local degradation of the basement membrane lining the venules followed by migration, alignment and proliferation of endothelial cells toward the angiogenic chemoattractant. Under normal conditions capillary proliferation is tightly controlled in adult tissues and occurs only during the female menstrual cycle in the follicle and corpus luteum, in the placenta during pregnancy, and as a result of bodily injury, such as during wound and fracture repair. A disruption of the balance between stimulatory and inhibitory influences on angiogenesis contributes to a variety of pathological conditions. Persistent angiogenicity occurs in diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, rheumatoid arthritis, hemangiomas, angiofibromas, psoriasis and atherosclerotic plaques, whereas insufficient capillary growth can result in delayed wound healing, nonhealing fractures, ischemia and fetal growth malformations such as hemifacial microsomia (Folkman et al., Science 235: 442-47 (1987)). Neovascularization is also one of the cardinal features that permit neoplastic progression. Tumor growth is critically dependent on new blood supply, and tumors cannot exceed a few millimeters in diameter in isolated perfused organs where capillary endothelium is degenerated (Folkman et al., Cancer 16: 453 (1963)).
Recent analysis of a variety of human cancers have shown that tumor progression occurs through the sequential deregulation and rearrangement of protooncogenes together with the inactivation of tumor suppressor genes. (Fearon et al, Cell 61: 759-67 (1990)). Whether any of these genetic alterations can trigger the disruption of control of angiogenesis in humans is unclear but at least four plausible scenarios can be envisaged which could result in escape from the factors regulating microvascular quiescence. First, these angiogenic factors may cause increased production of diffusible growth factors and cytokines that may either act directly as angiogenic factors to activate endothelial cells or indirectly through the recruitment of other cells that promotes neovascularization through the secretion of molecules with angiogenic potency. Second, they may cause the synthesis of enzymes that allow angiogenic factors such as bFGF to be released from extracellular matrix storages. Third, they may cause the stimulation of adjacent stromal and capillary endothelial cells to produce enzymes such as stromelysin and collagenase which induce basement membrane and extracellular matrix degradation and therefore, promote angiogenesis by allowing endothelial cell detachment and migration from the parent venules into the perivascular stroma. Finally, they may act to disrupt the local synthesis of physiologic inhibitors of angiogenesis.
Astrocytomas are an attractive model for investigation of the relationship between genes which are mutated during tumor. progression and angiogenesis. They are among the most dramatically neovascularized neoplasms with respect to vasoproliferation, endothelial cell cytology and endothelial cell hyperplasia (Brem et al., J. Natl. Canc. Inst. 48: 347-356 (1972)). The malignant progression of astrocytoma is histopathologically and clinically well characterized (Russell et al., Pathology of Tumors of the nervous system (Edward Arnold, London, 1989)) and this progression toward malignancy is accompanied by a well-documented sequential accumulation of genetic alterations (Cavenee et al., Mutat. Res. 247: 199-202 (1991)). Among these, the earliest known event is mutation of the p53 tumor suppressor gene and elimination of its
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Cavenee Webster K
Huang H.-J. Su
Van Meir Erwin
Caputa Anthony C.
Hayes Robert C.
Ludwig Institue for Cancer Research
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