Lipoxin analogs as novel inhibitors of angiogenesis

Details Lipoxin analogs as novel inhibitors of angiogenesis Lipoxin analogs as novel inhibitors of angiogenesis

2002-03-01

2003-09-30

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S560000, C514S549000, C514S552000, C514S543000

Reexamination Certificate

active

06627658

ABSTRACT:

BACKGROUND OF THE INVENTION
Angiogenesis is a fundamental process by which new capillaries are formed from existing blood vessels. This process plays important roles in physiological events such as formation of the corpus luteum, development of the embryo and wound healing, including recovery from both myocardial ischemia and peptic ulcer (1). Unregulated growth of blood vessels can contribute to tissue injury in a large number of diseases such as arthritis, diabetes, and tumor progression (2). Endothelial cells are normally quiescent and are activated during the angiogenic response. Upon stimulation, endothelial cells can degrade their basement membrane and proximal extracellular matrix, migrate directionally, then divide and organize into functional capillaries invested by a new basal lamina (3).
There is a growing body of evidence demonstrating that the angiogenic switch is regulated by the net balance between positive and negative regulators of new capillary growth (2). Persistence of neovascularization requires a pro-angiogenic environment, with the expression of angiogenic factors outweighing that of angiostatic factors. A range of peptides can influence this balance, including mitogenic factors such vascular endothelial growth factor (VEGF) (3), nonmitogenic factors (selected cytokines, CXC chemokines), and internal peptide fragments of angiostatin and endostatin (3). Certain eicosanoids also have potent biologic actions on vascular endothelial cells. In rabbits, PGE
2
, PGR
2&agr;
, and prostacylin (PGI
2
) stimulate angiogenesis where prostaglandin E series, in particular PGE
1
, is most potent. PGE
2
is a potent inducer of VEGF expression in synovial fibroblasts. In addition to its known vasodilator and antiplatelet properties, PGI
2
can also induce VEGF gene expression and protein synthesis (4).
It was recently reported that 12-lipoxygenase activity and one of its products, 12(S)-HETE, is required for angiogenic responses (5), and that P450-derived 12R-HETE stimulates angiogenesis via NF-kB (6). The cyclooxygenase-2 (COX-2) gene in endothelial cells is rapidly upregulated by several growth factors as well as inducers of angiogenesis (7). Along these lines, results using three different endothelial cell models show that COX-2 is an essential component of angiogenesis, at least in vitro (8). Nonsteroidal anti-inflammatory drugs such as aspirin (ASA) have been implicated in the prevention of certain cancers such as lung and colon cancer (9, 10) that might be related to ASA's ability to reduce angiogenesis (7).
A need therefore exists, for compositions and methods to prevent angiogenesis that are directed toward the disease process, such that angiogenesis is prevented or inhibited physiologically. A need also exists for compositions and methods that induce angiogenesis in tissue that is lacking the requisite or essential physiological requirements for sustainability.
SUMMARY
Proliferative states such as chronic inflammation, ischemic diseases and cancer are often accompanied by intense angiogenesis, a highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation and maturation. Aspirin-triggered lipoxins (ATL), the 15R enantiomeric counterparts of lipoxins (LXs), are endogenous mediators generated during multicellular responses that display potent immunomodulatory actions. Surprisingly, it has been discovered that LXs, ATLs, and more specifically, the ATL stable analogs, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A
4
(denoted ATL-1), LXA
4
, 15-epi-LXA
4
and 15-R/S-methyl, LXA
4
are potent inhibitors of angiogenesis. For example, ATL-1, LXA
4
, 15-epi-LXA
4
and 15-R/S-methyl, LXA
4
each inhibited endothelial cell proliferation in the 1-10 nM range by ~50% in cells stimulated with either vascular endothelial growth factor (VEGF) at 3 ng/ml or leukotriene D
4
(10 nM). In addition, ATL-1 (in a 10-100 nM range) inhibited VEGF (3 ng/ml)-induced endothelial cell chemotaxis. In a granuloma in vivo model of inflammatory angiogenesis, ATL-1 treatment (10 &mgr;g/mouse) reduced by ~50% the angiogenic phenotype, as assessed by both vascular casting and fluorescence. Together, these results identified a novel and potent previously unappreciated action of aspirin-triggered 15-epi-LX.
In one aspect, the present invention pertains to methods for the prevention, reduction or inhibition of angiogenesis. The method is accomplished by the administration of an effective amount of LXA
4
and analogs thereof, such as 15-R/S methyl, LXA
4
, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof. As a consequence of the action of the therapeutic agent, angiogenesis is prevented or inhibited in the subject.
In another aspect, the present invention also pertains to methods for the prevention or inhibition of angiogenesis. The method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA
4
, such as 15-epi-16-(para-fluoro)-phenoxy-lipoxin A
4
(ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof. As a consequence of the action of the therapeutic agent, angiogenesis is prevented or inhibited in the subject.
In still another aspect, the present invention pertains to methods for the prevention or inhibition of solid tumor tissue growth undergoing neovascularization in a subject. The method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA
4
, such as 15-epi-16-(para-fluoro)-phenoxy-lipoxin A
4
(ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof, to a subject in need thereof.
In another aspect, the present invention pertains to methods for the prevention or inhibition of solid tumor tissue growth undergoing neovascularization in a subject. The method is accomplished by the administration of an effective amount of LXA
4
and analogs thereof, such as 15-R/S methyl, LXA
4
, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
In yet another aspect, the present invention is directed to methods to inhibit or prevent neovascularization from occurring in a subject. The method is accomplished by the administration of an effective amount of LXA
4
and analogs thereof, such as 15-R/S methyl, LXA
4
, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
In yet another aspect, the present invention is directed to methods to inhibit or prevent neovascularization from occurring in a subject. The method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA
4
, such as 15-epi-16-(para-fluoro)-phenoxy-lipoxin A
4
(ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
The invention is also directed to methods for treating a subject in which neovascularization is occurring in retinal tissue. The neovascularization in the retinal tissue can be prevented or inhibited by administering an effective amount of LXA
4
and analogs thereof, such as 15-R/S methyl, LXA
4
, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
The present invention is further directed to methods for treating a subject in which neovascularization is occurring in retinal tissue. The neovascularization in the retinal tissue can be prevented or inhibited by administering an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA
4
, such as 15-epi-16-(para-fluoro)-phenoxy-lipoxin A
4
(ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
The invention is further directed to methods for treating a subject for restenosis in tissue wherein smooth muscle cell migration occurs following angioplasty. The restenosis can be prevented or inhibited by administering an effective amount of LXA
4

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