Current Pharmaceutical Design - Volume 13, Issue 35, 2007

Angiogenesis, a process of growing new vasculature from pre-existing vessels, is a phenomenon that is the focus of investigation of many laboratories. The pharmacological research targeting this process is related into two aspects, inhibition of pathological angiogenesis such as in cancer development, and therapeutic angiogenesis promoting a vessel growth during several cardiovascular disorders. Highly advance studies are performed on the angiostatic drugs, which target a variety of factors and biological molecules involved in the progression of neovascularization. Structurally, these pharmaceuticals are humanized monoclonal antibodies, short synthetic or recombinant peptides or peptidomimetics and biologically active chemical molecules. Many of these compounds have been isolated from natural sources. The most effective as angiostatic targets are pro-angiogenic growth factors (e.g. VEGF, FGF), receptors present on the surface of endothelial cells (e.g. integrins, growth factors receptors), and intracellular signaling molecules regulating the survival/death cell process (e.g. PKC-β, HIF-1). This issue of journal presents review articles showing the recent progress in development of anti-angiogenic therapy in cancer treatment as well as perspectives in the application of new targets for this therapy. Other papers will overview the application of biopolymers in tissue repair and stimulation of angiogenesis in this process. In the first paper [1] the authors overview the current stage of investigation of anti-angiogenic agents in therapy of malignant glioma. This brain tumor is considered as the most vascularized and extremely difficult to treat, because of the limited penetration of pathological tissue by oncostatic drugs. This phenomenon is related to the tight junction of the brain blood barrier, which makes designing an effective pharmaceutical for this tumor a big challenge. The promising clinical trials showed the application of anti-angiogenic therapy in combination with chemo- or radio-therapy. The angiostatic agents are usually well tolerated by the patients and further development of these drugs has good pharmaceutical perspectives. The next review by Silverstein and Febbraio [2] is devoted to the summary of current knowledge about the importance of thrombospondin in angiogenesis in the context of its interaction with e CD36, a cell membrane anchored receptor expressed on endothelial cells. The authors discuss the mechanisms occurring in endothelial cells following the binding of thrombospondin to CD36, that lead to the blocking of cells proliferation. The regulatory effect on angiogenesis in this system is complemented by the circulating histidine-rich glycoprotein (HRGP), which contains the CD36 homology domain. HRGP, by binding to thrombospondin, blocks its anti-angiogenic activities and in consequence promotes angiogenesis. This is a very interesting system for controlling angiogenesis. Its elements may be targeted for the modulation of pathological vascularization process or therapeutic angiogenesis. The role of annexin II in angiogenesis is discussed in the paper by Sharma and Sharma [3]. This is a multifunctional molecule appearing on the endothelial cell surface and on a variety of other cell types including cancer. It is receptors for plasminogen and tissue and urokinase plasminogen activators, tPA and uPA, respectively. Interestingly, annexin II also binds angiostatin, a fragment of plasminogen, which was characterized as a potent inhibitor of angiogenesis. Moreover, annexin II participates in the conversion of plasminogen to plasmin. This enzyme increases neovascularization and tumoral cells invasion processes by the degradation of extracellular matrix. Therefore annexin II appears to be an interesting pharmaceutical target for the protection of tissues against pathological angiogenesis. The review paper presented by Thijssen and his colleagues [4] summarizes the approaches for selective identification of target molecules on pathological endothelial cells that are activated during the progression of tumor or other angiogenesis-related disorders such as certain inflammatory diseases.....

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/ Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.

Thrombospondin (TSP)-1 and -2 are potent inhibitors of angiogenesis in vivo and of microvascular endothelial cell responses to angiogenic factors in vitro. The anti-angiogenic activity of thrombospondins is contained in a structural domain known as the TSP type I repeat or TSR. TSR domains are present in many other proteins, several of which have also been shown to have anti-angiogenic activity and a peptide-mimetic drug based on the domain is in clinical trials as an anti-angiogenic anti-cancer therapy. We have identified CD36 as the endothelial cell receptor for TSP-1 and -2 and showed that it is necessary for their anti-angiogenic activity. CD36-mediated antiangiogenic activity in endothelial cells is due to its ability to activate a specific signaling cascade that results in diversion of a proangiogenic response to an apoptotic response. Recently we identified a circulating protein, histidine-rich glycoprotein (HRGP), that contains a CD36 homology domain and that acts as a soluble decoy to block the anti-angiogenic activities of TSPs, thereby promoting angiogenesis. The tripartite interactions among CD36, TSR domains and HRGP in tissues may play an important role in regulating physiological and pathological angiogenesis.

It is well established that human tumors overproduce plasmin a serine protease that is known to promote angiogenesis, tumor growth and metastasis. However, the mechanism by which endothelial or tumor cells regulate the proteolytic activity of plasmin is not well understood. Cell surface receptors regulate activation of plasminogen to plasmin and its proteolytic activity. Annexin II is one of the well studied receptors for plasminogen and tPA, which binds to plasminogen and converts it to plasmin. Plasmin is a highly reactive enzyme which is physiologically involved in fibrinolysis. Since the proteolytic activity of plasmin is very tightly regulated, uncontrolled production of plasmin can degrade extracelluar matrix (ECM) and basement membrane (BM) of the surrounding blood vessels. Thus plasmin plays an important role in neoangiogenesis and cancer invasion and metastasis. Therefore, the receptor which regulates plasmin generation may be an attractive target for the development of anti-cancer/anti-metastatic agents. Angiostatin (AS), internal fragment of plasminogen, has been reported to inhibit human tumor growth and metastasis. We have shown that AS binds to endothelial/cancer cell surface annexin II with high affinity and interferes with plasmin generation suggesting that the role of plasmin/plasminogen system may be more complex than we previously thought. In this review we provide a comprehensive analysis of the literature in context of the role of annexin II in angiogenesis, tumor progression and metastasis. Compelling evidence from the literature and our own findings suggest that annexin II may be a potential target for the development of effective therapeutic strategies for the treatment of cancer and its induced metastasis.

The development of novel treatment strategies for therapy of angiogenesis-dependent diseases requires identification of specific tumor endothelial cell markers to which therapeutic agents can be targeted. This can be achieved by random or targeted approaches. Random approaches are based on genomic screening to identify differences between normal and activated endothelium. Targeted approaches utilize known angiogenesis inhibitors to find their molecular targets. Both approaches may lead to the development of angiostatic therapies that are directly targeted towards activated endothelial cells. This review summarizes the recent developments in both approaches.

Although anti- angiogenesis strategies have generated much enthusiasm for therapeutic applications, it is still unknown whether they would be feasible for prevention. The possibility of interfering very early in tumor progression by modulating the cancer angiogenic switch is appealing. In this chapter, we review progress with in vitro and in vivo models that show that anti-angiogenic interventions may be amenable to long- term chemopreventive measures. In particular, some approaches that are nearly ready for major applications are anti-oxidant nutraceuticals and copper deficiency. We use these strategies as paradigms of how to make progress in this difficult but important area of translational research.

Peripheral arterial occlusive disease (PAD) describes vascular disorders associated with ischemia and PAD affects about 8 million people in the United States. Moreover, PAD's prevalence can increase dramatically if cardiovascular disease is present. In healthy individuals reducing blood flow through the lower extremity is followed by a physiological process to limit ischemia in the distal tissue. This process is called revascularization and impairing revascularization results in PAD. Studies suggest nitric oxide (NO) maybe involved in the ischemia-dependent hindlimb revascularization process. NO is increased in the ischemic hindlimb and eliminating NO impairs the revascularization process. Moreover, restoring NO improves hindlimb revascularization. NO may be acting through its effects on vascular tone, cell migration, or extracellular matrix degradation. The present review illustrates nitric oxide's critical role in the ischemia-induced hindlimb revascularization. Thus, restoring normal NO levels in diseased arteries may represent a viable therapeutic avenue by supplementing exogenous NO or employing therapeutic strategies to either increase NO synthesis and its messengers or decrease NO catabolism.

Sufficient blood perfusion is essential for all tissues to guarantee nutrient- and gas exchange. As many diseases are induced by the reduction of blood perfusion such that these tissues gradually loose their ability to function properly, therapeutic angiogenesis aims to increase blood flow in ischemic tissues by stimulating the patient's endogenous capacity to develop new blood vessels. These studies include application of angiogenesis stimulating (growth) factors and adhesion sequences as well as local gene therapy. One approach is to rationally design 3D-fibrin hydrogel matrices that provide specific adhesion sequences such as a receptor for αvβ3- integrin expressed on angiogenic endothelial cells and that, in addition, are able to store and release angiogenic growth factors such as VEGF-A165 and bFGF that target cell type-specific responses. Moreover, these matrices can be modified to release complexed plasmid DNA that transfect surrounding cells and improve angiogenesis. During wound healing, cells infiltrate into the scaffold and degrade it, thereby releasing entrapped growth factors or complexed plasmid DNA, and with the speed of tissue regeneration the scaffold is completely removed when tissue healing is achieved. The long-term aim is to develop biomimetic 3D-matrices for applications in a biomaterials context that can be applied directly at the site of injury by minimal invasive surgery. 3D-fibrin matrices constitute a scaffold and release system for single or combined therapeutic biomolecules and may therefore be able to contribute to the patients' endogenous healing response resulting in the functional recovery of a diseased tissue or organ.

Angiogenesis, the development of blood vessels from the pre-existing vasculature, is a key component of embryogenesis and tissue regeneration. Angiogenesis also drives pathologies such as tumor growth and metastasis, and hemangioma development in newborns. On the other hand, promotion of angiogenesis is needed in tissues with vascular insufficiencies, and in bioengineering, to endow tissue substitutes with appropriate microvasculatures. Therefore, much research has focused on defining mechanisms of angiogenesis, and identifying pro- and anti-angiogenic molecules. Type I collagen, the most abundant protein in humans, potently stimulates angiogenesis in vitro and in vivo. Crucial to its angiogenic activity appears to be ligation and possibly clustering of endothelial cell (EC) surface α1β1/α2β1 integrin receptors by the GFPGER502-507 sequence of the collagen fibril. However, additional aspects of collagen structure and function that may modulate its angiogenic properties are discussed. Moreover, type I collagen and fibrin, another angiogenic polymer, share several structural features. These observations suggest strategies for creating “angiogenic superpolymers”, including: modifying type I collagen to influence its biological half-life, immunogenicity, and integrin binding capacity; genetically engineering fibrillar collagens to include additional integrin binding sites or angiogenic determinants, and remove unnecessary or deleterious sequences without compromising fibril integrity; and exploring the suitability of poly(ortho ester), PEG-lysine copolymer, tubulin, and cholesteric cuticle as collagen mimetics, and suggesting means of modifying them to display ideal angiogenic properties. The collagenous and collagen mimetic angiogenic superpolymers described here may someday prove useful for many applications in tissue engineering and human medicine.

Statins are pluripotent agents exhibiting multiple non-lipid-lowering actions. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely: a) osteoporosis and osteoporosis- related bone fractures, b) cancer, c) solid organ transplantation, d) cerebrovascular events (transient ischemic attack and stroke episodes), e) various neurological disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, f) cardiac arrhythmias and heart failure, g) renal diseases, h) rheumatoid arthritis, i) autoimmune diseases, j) sepsis, and k) allergic asthma. We reviewed the literature searching for studies that support or oppose the use of statins in each proposed indication. In some of these emerging indications, a role for statin treatment is more firmly set; for others, current evidence is more controversial. Future trials may reveal more convincing evidence that will make statin use necessary in the therapeutic management of several diseases.

There is now a large body of evidence that weight loss in older persons not only increases mortality, but also increases the incidence of hip fracture, functional deterioration and institutionalization. Weight loss is a central component of frailty. There is evidence that it is not only muscle, but also fat loss that leads to these deleterious effects. The reasons why fat loss can be harmful in older persons are reviewed. There are four major causes of weight loss in older persons viz. anorexia, sarcopenia, cachexia and dehydration. This review concentrates on the major causes of anorexia and sarcopenia. In particular, the emergence of new medications such as selective androgen receptor molecules, antimyostatin analogues, megestrol acetate (nanocrystal formulation), and ghrelin agonists are reviewed. The potential role of anabolic steroids is also discussed.