Peptide for inhibiting growth of smooth muscle cells

Details Peptide for inhibiting growth of smooth muscle cells Peptide for inhibiting growth of smooth muscle cells

1998-04-24

2001-02-20

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C514S014800, C530S326000

Reexamination Certificate

active

06191113

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel peptide which can inhibit growth of smooth muscle cells. The present invention also relates to a medicament for inhibiting growth of smooth muscle cells comprising said peptide.
BACKGROUND OF THE INVENTION
Smooth muscle cells are found in the media of aorta, the gastrointestinal tracts, the lung and the like. There are known diseases associated with extraordinary growth of smooth muscle cells, including arteriosclerosis, restenosis after angioplasty, luminal stenosis after grafting blood vessel, smooth muscle sarcoma and the like.
Arteriosclerosis is generally defined as a topical arterial lesion exhibiting intimal thickening, reconstruction, sclerosis or functional deterioration of the arterial wall and pathologically classified into three groups, i.e. micro-arteriosclerosis, calcification of the media and atherosclerosis. Among these three groups, atherosclerosis causes ischemic heart diseases, cerebral apoplexy or cerebral infarction and thus clinically most important. Atherosclerosis, when it occurred at the coronary artery, causes angina pectoris by narrowing the lumen, or leads to severe diseases such as unstable angina or myocardial infarction by forming thrombus in case of the rupture of atherosclerotic lesion. Atherosclerosis, when it occurred at the cerebral artery, also causes cerebral infarction or intracerebral bleeding, or leads to occlusive arteriosclerosis in case of the leg-governing arteries (from the aorta under the kidney to the common femoral artery). Thus, atherosclerosis is a cause of severe diseases.
As a mechanism of an onset of atherosclerosis, “Injury to Response” theory has widely been accepted today [Ross, R., Nature, 362, p801 (1993)]. That is, endothelial cells of blood vessel produce various growth factors which accelerate growth of smooth muscle cells when they are injured or given stimuli such as hyperlipidemia, viral infection or hypertension. As a result, smooth muscle cells grow to lead to intimal thickening.
For internally treating arteriosclerosis, a medicament for treating the risk factors such as an antihyperlipidemia or an antihypertensive has been administered, or a medicament for inhibiting the onset of arteriosclerosis such as an antioxidant, an antiplatelet, a vasodilator or an anticoagulant has been administered up till the present. However, these medicaments are not sufficiently effective in the clinical point of view.
For angina pectoris or myocardial infarction as caused by arteriosclerosis, some surgical treatments such as Percutaneous Transluminal Coronary Angioplasty, atherectomy, laser excision or stent implant have been employed and successful to some extent. Among these, Percutaneous Transluminal Coronary Angioplasty (PTCA) has widely been used to keep blood flow. PTCA has become popular soon as a radically curable means for treating angina pectoris and nowadays is one of established procedures for treating angina pectoris since it is more convenient than coronary artery bypass grafting (CABG), can easily be used repeatedly, and induces less postoperative complications even in the aged [Landau, C., N. Engl. J. Med., 330, p981 (1994)].
However, although there have been improvement of procedures or instruments or development of novel procedures in these PTCA and atherectomy angioplasties, a crucial problem still remains unsettled, i.e. restenosis is observed in 25 to 49% of those patients operated three to five months after operation. Since restenosis requires further treatment such as PTCA or CABG, it is a quite serious problem in view of burden to patients or financial difficulties of insurance. Although various drugs have been administered for the purpose of inhibiting the onset of restenosis, they are not sufficiently effective.
A mechanism of the onset of restenosis has been studied. Recent studies show that a cause of restenosis is growth of smooth muscle cells at the intima of blood vessel [Hanke, H. et al., Circulation Res., 67, p651 (1990)]. That is, it is estimated that restenosis is caused by growth of smooth muscle cells in blood vessel which occurred to repair the structure of blood vessel physically destroyed by, for example, balloon catheter but unrestrictedly proceeded. Thus, there has been an attempt to treat restenosis by inhibiting growth of smooth muscle cells at the restenosed site, including a clinical test with heparin [Ellis, S. G. et al., Am. Heart J., 117, p777 (1989)], a clinical test with a combination of aspirin and dipyridamole [Schwartz, L. et al., N. Engl. J. Med., 318, p1714 (1988)], and the like. However, none of these could effectively inhibit restenosis.
Furthermore, in addition to coronary angioplasty as mentioned above, an operation of grafting self blood vessel from other portions (internal thoracic artery, gastroepiploic artery, and great saphenous vein are mainly used), i.e. coronary artery bypass, has clinically been used to reconstruct blood flow for coronary artery where excess stenosis or occlusion has occurred as a cause of ischemic heart diseases. However, even in coronary artery bypass, intimal thickening of the grafted blood vessel frequently occurs to stenose the lumen of said grafted vessel to interrupt blood flow, and hence, it is not clinically reliable. It was reported that growth of smooth muscle cells and production of extracellular matrix associated therewith plays a central role in such intimal thickening [Toshinobu Horie, Nippon Rinsho, 52, p1010 (1994)], and thus, patency of the graft for a long period of time is expected by inhibiting growth of smooth muscle cells. In addition, not limited to coronary artery, graft of self blood vessel for the injured ones is commonly employed in case of surgical injury of extremities in the field of plastic surgery. It is known that luminal stenosis caused by growth of smooth muscle cells frequently occurs particularly at the anastomotic sites with normal blood vessel.
In case of grafting blood vessel, an artificially prepared blood vessel (hereinafter referred to as “artificial vessel”) is also used for the graft in place of self blood vessel from other portions. The artificial vessel is used not only for coronary artery but also for other vessels, including for example, for injured blood vessel after amputation of extremities, as blood vessel for AV shunt in patients with artificial dialysis, and the like. However, even in case of an artificial vessel, it is also known that intimal thickening frequently occurs at the anastomotic site with normal blood vessel to interrupt blood flow [Toshiya Shindo et al., Jinko Zoki, 22, p459 (1993)]. For both self blood vessel and an artificial vessel, a drug which can effectively inhibit growth of smooth muscle cells has not yet been found and thus there is a desire to develop such drug.
Smooth muscle sarcoma, smooth muscle cells-derived malignant tumor, mainly appears at the uterus and the gastrointestinal tract as well as the posterior peritoneum and the subcutaneous soft tissue, grows destructively and invasively, and usually metastasizes to the lung through blood circulation. Smooth muscle sarcoma has been treated by surgical excision in combination with administration of a usual anti-cancer agent. However, a usual anti-cancer agent exhibits unacceptable side effects, and hence, there is a desire to develop a drug which can specifically inhibit growth of smooth muscle cells.
DISCLOSURE OF THE INVENTION
Under the circumstances, in order to find out a substance which can effectively inhibit arteriosclerosis and restenosis after Percutaneous Transluminal Coronary Angioplasty or other angioplasties, the present inventors have searched for an accelerating factor and an inhibiting factor for restenosis using a model animal for intimal thickening of blood vessel prepared by balloon injury and a culture of blood vessel smooth muscle cells. As a result, the present inventors have already found that a tissue factor pathway inhibitor (TFPI) exhibited a quit

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