Integrins

Note LFA-1 = lymphocyte function-associated molecule, VLA-4 = very late antigen 4 see text for details. 

After the initial attachment of neutrophils to the endothelium via the selec-tins, the next stage in the process is performed via the integrins. L-selectin on the neutrophil surface is shed (the shed molecule being some 8-10 kDa smaller than the bound molecule) via a process that probably involves proteolytic cleavage. The major groups of integrins present on leukocytes are shown in Table 3.2 further properties of these molecules are given later. 

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Table appendix Adhesion Molecules Anti-integrins... 

Interference with specific cell-cell and cell-matrix adhesion mechanisms is another rapidly advancing approach to therapeutically interfere with angiogenesis. Antagonistic antibodies (Vitaxin) to the integrin heterodimer av 33 have been shown to act on the blood vessels of tumors but not on the resting organ vasculature. Vitaxin demonstrated some promise in Phase II clinical trials. 

The role of integrins has been found in various pathological processes, including angiogenesis,... 

The largest numbers of integrins are members of the (31 integrins, also known as the very late antigen (VLA) subfamily because of its late appearance after activation. There are at least seven receptors characterized from this subfamily, each with different ligand specificity. Among the most studied include the 04(31 and a5 31 receptors. The leukocyte integrin a4 31 is a cell adhesion receptor that is predominantly expressed on lymphocytes, monocytes and eosinophils. 

Potent and Selective Small Molecule Antagonists of ol4/31 Integrins... 

Recent studies suggested a key role for a5(31 integrin in certain bacterial invasion of human host cells leading to antibiotic resistance [5]. 

GPIIb/IIIa Integrin Receptor Antagonists In the Rapid Diagnosis of Thromboembolic Events... 

The role of the platelet integrin GPIIb/IIIa receptor and its potential utility as a radio-diagnostic agent in the rapid detection of thromboembolic events has been demonstrated [6]. This approach may be useful for the noninvasive diagnosis of various thromboembolic disorders. 

Integrin otvfi3 Antagonists Promote Tumor Regression by Inducing Apoptosis of Angiogenic Blood Vessels... 

Antagonists of integrin av 33 inhibit the growth of new blood vessels into tumors cultured on the chick chorioallantoic membrane without affecting adjacent blood vessels, and also induce tumor regression [7]. Antagonists of av 33 also inhibit angiogenesis in various ocular models of retinal neovascularization [7]. 

The calcification of atherosclerotic plaques may be induced by osteopontin expression, since osteopontin is a protein with a well-characterized role in bone formation and calcification. Vascular smooth muscle cell migration on osteopontin is dq endent on the integrin av 33 and antagonists of av 33 prevent both smooth muscle cell migration and restenosis in some animal model [8]. 

Integrin olv/33 Antagonists Versus Anti- otvfi3 and avfi5... 

Since the recognition of at least two av integrin pathways for cytokine-mediated angiogenesis, av 33 and av 35 antagonists may be more effective in certain indications as compared to a specific anti- av 33. However, further work is needed to document this notion. 

RGD analogs have been shown to inhibit the attachment of osteoclasts to bone matrix and to reduce bone resotptive activity in vitro. The cell surface integrin, av 33, appears to play a role in this process. RGD analogs may rq resent a new approach to modulating osteoclast-mediated bone resorption and may be useful in the treatment of osteoporosis [9]. 

Therapeutics A number of potent small molecule antagonists for av 33 integrin are under preclinical investigations for various angiogenesis or vascular-mediated disorders [10]. 

Site directed delivery This approach of conjugating av 33 integrin ligand with a chemotherapeutic agent for optimal efficacy and safety in cancer is under investigation. Earlier work demonstrated the validity of this concept [10]. 

Cue D, Southern S, Southern P et al (2000) A non-peptide integrin antagonist can inhibit epithelial cell ingestion of streptococcus pyogenes by blocking a5 31 -fibronectin-Ml protein complexes. Proc Nat Acad Sci 97(6) 2858-2863... 

Friedlander M, Brooks PC, Shaffer R et al (1995) Definition of two angiogenic pathways by distinct av integrins. Science 27 1500-1502... 

Srivatsa SS, Tsao P, Holmes DR et al (1997) Selective av(33 integrin blockade limits neointima hyperplasia and lumen stenosis in stented porcine coronary artery injury in Pig. Cardiovasc Res 36 408-428... 

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