Antiangiogenic drugs

Details Antiangiogenic drugs Antiangiogenic drugs

1999-02-11

2002-12-10

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S014800, C514S016700, C530S309000, C530S311000, C530S324000, C530S327000, C530S328000

Reexamination Certificate

active

06492330

ABSTRACT:

FIELD OF INVENTION
The invention relates to the use of peptides individually or in combination, for treating and/or preventing angiogenesis. It also relates to the use of a combination of peptides referred to as MuJ-7 as an anticancer drug in restricting tumor growth and its spread by inhibiting tumor angiogenesis. MuJ-7, in addition inhibits metastasis through its antiangiogenic activity in all cancers. The invention also relates to a pharmaceutical composition containing either individual peptides or combinations of peptides, and methods of treatment of human beings and animals for curing and/or preventing angiogenesis.
BACKGROUND OF THE INVENTION
Angiogenesis is the growth of new microvessels. This process depends mainly on locomotion, proliferation, and tube formation by capillary endothelial cells. During angiogenesis, endothelial cells emerge from their quiescent state and can proliferate as rapidly as bone marrow cells, but unlike the bone marrow, angiogenesis is usually focal and of brief duration. Pathologic angiogenesis, while still a focal process, persists for months or years. The angiogenesis that occurs in diseases of ocular neovascularisation, arthritis, skin diseases, and tumors rarely terminates spontaneously and has until recently, been difficult to suppress therapeutically. Therefore, the fundamental goal of all antiangiogenic therapy is to return foci of proliferating microvessels to their normal resting state, and to prevent their regrowth
1
.
Although the molecular mechanisms responsible for transition of a cell to angiogenic phenotype are not known, the sequence of events leading to the formation of new vessels has been well documented
2,3
. The vascular growth entails either endothelial sprouting
3,4
or intussusception
5
. In the first pathway, the following sequence of events may occur: (a) dissolution of the basement of the vessel, usually a postcapillary venule, and the interstitial matrix; (b) migration of endothelial cells toward the stimulus; (c) proliferation of endothelial cells trailing behind the leading endothelial cell(s); (d) formation of lumen (canalization) in the cndothelial array/sprout; (e) formation of branches and loops by confluence/anastomoses of sprouts to permit blood flow; (f) investment of the vessel with pericytes; and (g) formation of basement membrane around the immature vessel
2,3
. New vessels can also be formed via the second pathway: insertion of interstitial tissue columns into the lumen of preexisting vessels. The subsequent growth of these columns and their stabilization result in partitioning of the vessel lumen and remodelling of the local vascular network
5,6
.
The rationale for antiangiogenic therapy is that progressive tumor growth is angiogenesis-dependent
8
. The switch to the angiogenic phenotype appears to be an independent event that occurs during the multistage progression to neoplasia
9
. The angiogenic switch itself, while relatively sudden and well localized, is nonetheless a complex process. This phenotype is currently understood in terms of a shift in the net balance of stimulators and inhibitors of angiogenesis, during which inhibitors are down regulated
10,11
.
Once new capillary loops converge toward a small in situ carcinoma or a microscopic metastasis, the tumor cells are bathed in additional survival factors and growth factors, not only from the circulating blood (perfusion effect) but also from vascular endothelial cells themselves (paracrine effect). The positive regulators of angiogenesis include at least 14 angiogenic proteins that have been discovered during the past 12 years and which have been sequenced and cloned
12
. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are the most well studied and are found in a majority of different types of human tumors. During the angiogenic switch one or more of these angiogenic stimulators is upregulated and it appears, however, that this up regulation of angiogenic stimulators is accompanied by down regulation of local tissue inhibitors of angiogenesis.
The paracrine stimulation of tumor cells by products from endothelial cells also operates in the other direction. Endothelial cell survival and growth are driven by tumor derived mitogens and motogens. These findings have led to a model of tumor growth in which the endothelial cell compartment and the tumor cell compartment interact with each other. They not only stimulate each other's growth, but if the endothelial cells are made unresponsive to angiogenic stimuli from the tumor cells, by administration of a specific endothelial inhibitor, both primary tumors
11
and metastatic tumors
10
can be held dormant, at a microscopic size. One could take advantage of this difference between endothelial cells and tumor cells by administering an angiogenesis inhibitor together with conventional cytotoxic chemotherapy up to the point at which the cytotoxic therapy would normally be discontinued because of toxicity or drug resistance. The angiogenesis inhibitor(s) could then be continued (for years), to maintain either stable disease or tumor dormancy
1
. Such combinations of antiangiogenic and cytotoxic therapy in tumor-bearing animals have been curative, whereas either agent alone is merely as inhibitor
15
.
Peptides/Proteins have previously been studied for antiangiogenic activity. Thrombospondin-1 (TSP-1) which is a naturally occurring inhibitor of angiogenesis, makes endothelial cells unresponsive to a wide variety of inducers. Both native TSP-1 and small antiangiogenic peptides derived from it show that this inhibition is mediated by CD36
16
(Dawson et al., 1997). Both IgG antibodies against CD36 and glutathione-S-transferase-CD36 fusion proteins that contain the TSP-1 binding site blocked the ability of intact TSP-1 and its active peptides to inhibit the migration of cultured microvascular endothelial cells.
The family of tissue inhibitors of metalloproteinases (TIMPs) are known to be specific inhibitors of matrix metalloproteinases (MMPs). The local balance between MMPs and TIMPs is believed to play a major role in extracellular matrix (ECM) remodelling during diseases such as cancer. TIMP-3 which is unique in being a component of ECM, inhibits endothelial cell migration and tube formation in response to angiogenic factors
17
(Anand-Apte et al., 1996).
The conditioned medium of human promyelocytic leukemia (HL6O) cells has been shown to contain a cell growth inhibitory factor, human cytostatin. Human cytostatin can inhibit endothelial cell proliferation, migration and microvessel tube formation on Matrigel-coated surfaces
18
(Yeung AK et al., 1996). Furthermore the anti-angiogenic effect of human cytostatin has been demonstrated on the chick chorioallantoic membrane. Human cytostatin can inhibit new blood vessel development, but cannot regress existing blood vessels.
Angiostatin, which is a 38 kD internal fragment of plasminogen is an antiangiogenic endothelial cell inhibitor and suppresses the growth of primary Lewis lung carcinoma in vivo
19
(Wu, Z. et al., 1997).
Thalidomide has recently been shown to antagonize basic fibroblast growth factor-induced angiogenesis in the rat corneal micropocket assay. It has been suggested that thalidomide elevates tumor hypoxia in the Lewis lung tumor, presumably via an antiangiogenic mechanism
20
(Minchinton AI et al., 1996).
One study examined the in vitro antiangiogeneic effects of the somatostatin analog octreotide on the growth of human umbelical vein endothelial cells (HUVEC) and vascular cells from explants of rat aorta cultured on fibronectin-coated dishes or included in fibrin gel. A total 10
−9
M octreotide reduced the mean uptake of
3
H-thymidine by HUVEC cells by 37% compared with controls. The 10
−8M
concentration of octreotide inhibited the proliferation of endothelial and smooth muscle cells growing on fibronectin by 32.6% and reduced the sprouting of cells from the adventitia of aortic rings in fibrin by 33.2% compared with controls, as measured by tetrazolium bioreduction and image analysis,

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