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Angiogenesis and its therapeutic opportunities.

1. Introduction

The growth of new capillaries from existing blood vessels, which is called angiogenesis, is mediated by a complex multistep process comprising a series of cellular events that lead to neovascularization [1, 2]. Angiogenesis plays a central role in various physiological processes within human body, not only during fetal development but also in tissue repair after surgery or trauma. Angiogenesis can be a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases [3-5]. The realization that tumor growth is associated with new blood vessels led us to investigate the chemical factors that mediate angiogenesis, broadened our knowledge of pathological processes, and thus opened new possibilities for the diagnosis and treatment of these diseases.

The pivotal process of angiogenesis can be simply described as multiple steps. First, angiogenic stimuli cause increased endothelial cell (EC) permeability and cellular proliferation, which continues as the new capillary sprout elongates [6]. Second, proteolysis of basement membrane matricellular components is a necessary process to promote the invasion of ECs into the stroma of the neighboring tissue [7], in which the cooperative activity of the plasminogen activator (PA) system and matrix metalloproteinases (MMPs) is required. Third, migrated ECs trigger lumen formation as the sprout forms a multicellular structure. Then, a new capillary channel is formed. Finally, the capillary is stabilized through the construction of basement membrane, adherent junctions, and ECs (Figure 1).

A number of molecules are involved in these complex angiogenic cascades. Their names and functions are described briefly in the next section and are listed in Table 1. These factors are commonly used as the targets in strategies to manipulate angiogenesis. The pathological disruption of angiogenesis can be caused by either vascular insufficiency (myocardial or critical limb ischemia) or vascular overgrowth (hemangiomas, tumors, and retinopathies) (Table 2). Thus, therapeutic benefits may be realized by manipulating angiogenesis.

2. Angiogenic Factors and Regulation of Angiogenesis

In recent decades, numerous studies focused on identifying angiogenesis stimulators, which led to the identification of several angiogenic factors. Angiogenic factors can be categorized as follows: (1) soluble growth factors such as acidic and basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor (VEGF), which are associated with EC growth and differentiation [8-10]; (2) inhibiting factors that inhibit the proliferation and enhance the differentiation of ECs, such as transforming growth factor [beta] (TGF-[beta]), angiogenin, and several low molecular weight substances [11-13]; and (3) extracellular matrix-bound cytokines that are released by proteolysis, which may contribute to the regulation of angiogenesis and include angiostatin, thrombospondin, and endostatin [14-18]. In addition, a number of microphages secreting bFGF, tumor necrosis factor (TNF), and VEGF were shown to be associated with tumor angiogenesis. Angiogenesis is governed by a balance between inducers and inhibitors [19]. It also can be regulated by EC proliferation, which is regulated or restrained by pericytes through the sequestration of potent mitogens in the extracellular matrix, changes in EC shape that reduce the sensitivity of the cells to growth factors, and certain endothelial integrins.

3. Angiogenic Disorders

The hypervascularity of tumors was first thought to be the inflammatory vasodilation of preexisting vessels in response to tumor metabolites and necrotic tumor products. It was also thought that tumor growth and metastasis depended on angiogenesis and that the tumor secreted the chemicals that shifted resting ECs into rapidly growing ECs. These ideas are not widely accepted yet. The concept of the role of angiogenesis in cancer and other diseases has now become clear.

3.1. Angiogenesis in Cancer. Most tumors (up to 2-3 [mm.sup.3]) persist in situ without neovascularization for months to years, but they become vascularized by "switches" in cells during the turnover to an angiogenic state when the tumor needs to keep growing. Cells in prevascular tumors may replicate as rapidly as those in expanding vascularized tumors; however, without the growth of new vessels, their growth is limited. A change in the local equilibrium between positive and negative angiogenic regulators of the growth of microvessels is involved in the switch to the angiogenic state [20, 21]. Of the angiogenic inducers (Table 1), those that are most commonly found in tumors appear to be VEGF and bFGF. Their angiogenic activities are synergistic [22]. VEGF plays a critical role in vasculogenesis and angiogenesis during fetal development. In a knockout mouse model, VEGF or VEGF receptor (VEGFR) inactivation resulted in defects in vasculogenesis in the early stages of development and was embryonic lethal [23].

VEGF is overexpressed in tumor stromal cells as well as tumor cells of renal cancer [24], lung cancer [25], breast cancer [26], and ovarian cancer [27]. VEGF expression is regulated positively by oncogenes such as Ras [28] and negatively by tumor suppressors such as von Hippel-Lindau (VHL) [29]. VEGF binds to VEGFR1 or VEGFR2 on the EC surface. Most of the angiogenic effects of VEGF result from VEGFR2 activation. Hypoxia is a major stimulator of VEGF expression that results from hypoxia-inducible factor 1 (HIF-1) binding to a hypoxia response element (HRE) within the VEGF promoter. It is also stimulated by inflammatory mediators (interleukin 1 (IL1), TGF-[beta], and prostaglandin E2 (PGE2)) or mechanical forces (shear stress and cell stretch). Increased PGE2 by cyclooxygenase-2 (COX-2) induces VEGF expression and angiogenesis in tumor cells or tumor stromal cells [30]. FGF signaling maybe through the recruitment of other growth factor signaling pathways. The simultaneous VEGF signaling through VEGFR1 was required in the bFGF-stimulated capillary organization. bFGF also initiates the transcription of hepatocyte growth factor (HGF) [31]. However, the upregulation of an angiogenic inducer is not sufficient for tumor angiogenesis. The downregulation of certain negative regulators or inhibitors (Table 1) for vessel growth maybe required [21].

Tumor growth is augmented by the onset of neovascularization through a perfusion effect and a paracrine effect. The perfusion effect is more efficient at allowing nutrients and oxygen to enter and catabolites to exit in crowded tissues, and the paracrine effect results from the production of growth factors (e.g., bFGF, insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), and granulocyte colony stimulating factor (GCSF)) by ECs or their release by macrophages and other host cells that are delivered to the tumor by blood vessels. Neovascularization gradually reduces a tumor's accessibility to chemotherapeutic drugs because tumors compress their blood supply. Antiangiogenic therapy in rodents showed increased delivery of chemotherapy agents to a tumor [32], which may be associated with lowered interstitial pressure and an unpacked mass of tumor cells.

3.2. Angiogenesis in Other Diseases. Either excessive or deficient angiogenesis can be classified as an angiogenic disease, which is an abnormal growth of microvessels (Table 2). Recent studies reported that the angiogenic protein VEGF is the chief mediator of ocular neovascularization, a major cause of blindness worldwide [33,34]. The upregulation of VEGF is a response to the local hypoxia that is produced in tumors by vascular compression and ischemia. Thus, a similar process may cause the formation of collateral vessels in an ischemic heart or limb. Neovascularization in atherosclerotic plaques [35] may be mediated by the overexpression of VEGF and by local hypoxia, which contribute to the growth and rupture of plaques. The expression of both VEGF and bFGF is excessive in hemangiomas of infancy. In the case of rheumatoid arthritis, infiltrated macrophages, immune cells, or inflammatory cells produce excessive angiogenic factors that may mediate the ingrowth of a vascular pannus in a joint [36]. In psoriasis, hypervascular skin lesions over expressed the angiogenic polypeptide IL8 and under expressed the angiogenic inhibitor thrombospondin 1 (TSP-1) [37]. Peptic ulcers in animals appear to be deficient in microvessels in the ulcer bed. The oral administration of aFGF induced angiogenesis in the ulcer bed and accelerated the healing of ulcers in animals [38]. Bowel atresia, vascular malformations, hemangiomas, and unilateral facial atrophy are developmental disorders that are caused also by abnormal vascular development through defects in angiogenesis [39].

4. Angiogenesis in Clinical Applications

Abnormal angiogenesis is the major cause of numerous diseases; therefore, angiogenesis itself can be useful for diagnostic/prognostic applications and can be manipulated for further clinical applications. In the case of ischemic diseases, which develop because of deficient angiogenesis, an angiogenesis stimulator can be used to induce therapeutic angiogenesis. In the case of cancer, which has excessive angiogenesis, angiogenic inhibitors including antiangiogenic factors can be used to attenuate angiogenesis. The Food and Drug Administration (FDA) approved becaplermin (Regranex, recombinant human PDGF-BB) for diabetic foot ulcer disease in 1977, which was the first angiogenesis-stimulating drug that was used as a therapeutic angiogenesis approach. For cancer therapeutics, the FDA approved bevacizumab (Avastin, humanized anti-VEGF monoclonal antibody), an angiogenesis inhibitor, to treat metastatic colorectal cancer in 2004 [40].

4.1. Diagnostic and Prognostic Applications. The quantitation of angiogenesis in a biopsy specimen may help predict the risk of metastasis or recurrence. The quantitation of microvessel density in histologic specimens of invasive breast cancer, for example, has provided an indication of the risk of metastasis [41]. A positive association between tumor angiogenesis and the risk of metastasis, tumor recurrence, or death has also been reported with regard to breast cancers and other types of tumors [42-44]. A high microvessel density may be a successful predictor of metastatic risk. An increased area of the vascular surface because of a high density may facilitate the escape of cancer cells into the circulation. An angiogenic cell that is shed from a primary tumor is more likely than a nonangiogenic cell to develop into a detectable metastasis.

The quantitation of angiogenic proteins in body fluids can be used to indirectly measure angiogenic activity. Higher concentrations of bFGF were found in the serum and urine of nearly 10% and more than 37% of cancer patients, respectively [45]. Concentrations of biologically active bFGF were abnormally high in the cerebrospinal fluid of children with brain tumors but not in children with hydrocephalus or malignant disease outside the central nervous system [46].

4.2. Therapeutic Angiogenesis. Therapeutic angiogenic drugs that accelerate the angiogenesis process are useful for treating diseases of deficient angiogenesis. In preclinical studies, orally administered bFGF was shown to stimulate angiogenesis and to accelerate the healing of duodenal ulcers in rats [38]. Phase I clinical trials were then prompted to evaluate this therapy in patients with gastric or duodenal ulcers that were refractory to conventional therapy [47]. Orally administrated bFGF was found to heal gastric ulcers that were caused by nonsteroidal anti-inflammatory drugs. Orally administrated aFGF induced angiogenesis in the ulcer bed and accelerated the healing of ulcers in animals 38].

A phase I clinical trial of therapeutic angiogenesis using bFGF protein in heparin-alginate slow-release microcapsules in 8 patients with symptomatic, severe coronary artery disease that was not amenable to complete revascularization by either percutaneous transluminal coronary angioplasty or coronary artery bypass grafting demonstrated the feasibility and safety of bFGF administration for coronary artery diseases [48]. These clinical studies suggest that angiogenic and other growth factors can heal gastrointestinal ulceration as well as coronary artery diseases. It is interesting to note that the antiulcer drug sucralfate (sucrose aluminum sulfate or Carafate) appears to act by protecting endogenous mucosal bFGF from degradation by acid.

Angiogenic agents can be used in ischemic heart disease as a therapeutic angiogenesis approach for cardiac tissue repair and regeneration [49, 50]. The therapeutic goal of this condition is to stimulate angiogenesis to improve perfusion, deliver survival factors to sites of tissue repair, mobilize regenerative stem cell populations, and ultimately restore form and function to the tissue. Although more than 2,000 patients with heart disease have received some form of experimental angiogenic therapy [51, 52], currently there are no FDA-approved angiogenic drugs to treat ischemic cardiovascular disease. The first FDA-approved device to stimulate new blood vessel growth in diseased hearts is a laser that is used in a technique called direct myocardial revascularization (DMR) or transmyocardial revascularization (TMR).

5. Antiangiogenic Therapies

Many studies using ECs that were isolated from either capillaries or large vessels led to considerable insights into the molecular and cellular biology of angiogenesis and the discovery and evaluation of potential antiangiogenic compounds (Table 3). They were identified using classical angiogenesis assays such as the chick chorioallantoic membrane (CAM), rabbit cornea assay, sponge implant models, and matrigel plugs [53-57]. Recent research has focused on the specific effects of antiangiogenic compounds on individual angiogenic processes. In this section, we discuss their clinical applications as antiangiogenic therapies.

5.1. Interferon Alpha-2a to Treat Hemangiomas. Hemangiomas occur in 1 out of 100 neonates and in 1 out of 5 premature infants [58]. Most do not need treatment because these tumors grow rapidly in the first year of life (the proliferating phase), slow down during the next 5 years (the involuting phase), and gradually regress by the age of 10-15 years (the involuted phase). However, about 10% of them may have serious tissue damage that includes interfering with a vital organ, obstructive airway, heart failure, or Kasabach-Merritt syndrome. Kasabach-Merritt syndrome, a platelet-trapping thrombocytopenic coagulopathy, and hepatic hemangiomas have a mortality rate of 30%-50%. Corticosteroid therapy worked for 30% of hemangiomas [59]. Radiation, cyclophosphamide treatment, and embolization were also tried and showed favorable outcomes; however, sometimes they showed toxicity. Interferon alpha-2a (IFN[alpha]-2a) is an angiogenic agent that could be useful for treating these hemangiomas. It was successfully used in a 7-year-old child with pulmonary hemangiomas [60]. It was also found that therapy with IFN[alpha]-2a accelerated the tumor regression in 18 of 20 hemangioma patients [61]. IFN[alpha]-2a suppresses the production of FGFs in human tumor cells, which could work for hemangiomas because bFGF is an angiogenic factor that is overexpressed in hemangiomas.

5.2. Ocular Neovascularization. Ophthalmology angiogenesis in the eye, an ocular neovascularization, includes age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), diabetic macular edema (DME), neovascular glaucoma, corneal neovascularization (trachoma), and pterygium. Inhibiting VEGF is presently an antiangiogenic therapy that is approved for ophthalmic conditions. Two currently approved antiangiogenic therapies for ophthalmic diseases are an anti-VEGF aptamer (pegaptanib, Macugen) and a Fab fragment of a monoclonal antibody directed against VEGF (ranibizumab, Lucentis). A photodynamic therapy called Visudyne (QLT Therapeutics/CIBA Vision) has shown effectiveness for treating macular degeneration and was the first FDA-approved blood vessel therapy for eye disease in 2004 [62, 63].

5.3. Rheumatoid Arthritis. Clinical trials of angiogenic inhibitors have not been performed yet in patients with arthritis; however, minocycline and TNP-470 (also known as AGM-470) have shown efficacy as potent inhibitors of the vascular pannus in experimental arthritis [36, 64].

5.4. Cancer. Angiogenesis plays a critical role in the growth and spread of cancer because a blood supply is necessary for tumor growth and metastases. Tumors secrete chemical signals that stimulate angiogenesis and thus stimulate nearby normal cells. Therefore, many natural or synthetic angiogenesis inhibitors, also called antiangiogenic agents, have been studied to prevent or slow the growth of cancer. These inhibitors can interfere with angiogenesis in various ways. Bevacizumab (Avastin) is a monoclonal antibody that specifically recognizes and binds to VEGF, which prevents VEGF from activating VEGFR [40]. In contrast, other angiogenesis inhibitors, including sorafenib and sunitinib, bind to receptors on the ECs or to other proteins in the downstream signaling pathways to block their activities [65].

Bevacizumab was FDA-approved to be used alone to treat glioblastoma and tobe used in combination with other drugs to treat metastatic colorectal cancer, some nonsmall cell lung cancers, and metastatic renal cell cancer. Bevacizumab is the first approved angiogenesis inhibitor that was shown to slow tumor growth and, more importantly, to extend the lives of patients with some cancers. The other FDA-approved antiangiogenic drugs are sorafenib (Nexavar) for hepatocellular carcinoma and kidney cancer, sunitinib (Sutent) for kidney cancer and neuroendocrine tumors, pazopanib (Votrient) for kidney cancer and neuroendocrine tumors, and everolimus (Afinitor) for kidney cancer. Researchers are exploring the use of angiogenesis inhibitors in some clinical trials (Table 4).

5.5. Conventional Anticancer Therapy versus Antiangiogenic Therapy. Conventional anticancer therapy generally faces the problems of drug resistance and impaired drug delivery because of genomic instability and the tumor mass of cancers [66]. Tumor mass has an interstitium composed of a collagen-rich matrix between cancer cells and vascular cells. Anticancer drugs need to pass through the interstitium from blood vessels to reach the cancer cells. However, tumor mass has an interstitium with an abnormally high interstitial fluid pressure, which acts as a barrier to drug delivery. However, angiogenesis inhibitors inhibit the growth of blood vessels rather than tumor cells. In some cancers, angiogenesis inhibitors are most effective when they are combined with additional therapies, especially chemotherapy. It has been hypothesized that these drugs help normalize the blood vessels that supply the tumor, facilitating the delivery of other anticancer agents [32]. Angiogenesis inhibitor therapy may prevent tumor growth instead of killing tumors. Therefore, antiangiogenic therapy may require a long period for treatment.

6. Concluding Remarks and Prospects

Currently, chemotherapeutic drugs are being used to treat cancer as well as other diseases. Unfortunately, many compounds showed limited efficacy with impaired delivery, penetration, and selectivity for the tumor cells, thereby causing serious side effects and bystander effects. The activity of these compounds is mainly restricted by the drug resistance of tumor cells. Preclinical studies and clinical trials suggest that angiogenesis-based therapy may be useful in the future care of patients. In particular, antiangiogenic therapy is a unique approach to kill tumor cells because it does not directly target cancer cells; instead, it inhibits the growth of blood vessels. So far, antiangiogenic agents are not likely to result in bone marrow suppression, gastrointestinal symptoms, or hair loss. The approach to slow the growth of blood vessels may require several months to a year; thus, the administration of the agents at lower doses and longer uninterrupted periods than the usual doses and periods of conventional cytotoxic agents should be considered in the design of clinical trials. The development of resistance to angiogenic inhibitors has not been a big problem so far. Furthermore, a combination of antiangiogenic therapy and conventional therapy may be more effective than either therapy alone. Angiogenesis-based therapy may provide a novel, selective, safe, and reasonable treatment in future medicine.

http://dx.doi.org/10.1155/2013/127170

Conflict of Interests

The authors declare that there is no conflict of interests.

Acknowledgment

This work was supported by Grants from the National Research Foundation funded by the Korean government (MEST: 2010-0020260, 20120618, 2012M3A9C6049720; MSIFP: 2013R1A1A3008484).

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So Young Yoo and Sang Mo Kwon

Laboratory for Vascular Medicine and Stem Cell Biology, Convergence Stem Cell Research Center, Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea

Correspondence should be addressed to Sang Mo Kwon; smkwon323@pusan.ac.kr

Received 12 March 2013; Accepted 7 July 2013

Academic Editor: Grzegorz Szewczyk

TABLE 1: Overview of the different angiogenic factors.

Category          Names

Proteolytic       (i) Matrix metalloproteinases
enzymes           (MMPs): matrilysin (MMP-7),
                  interstitial collagenase (MMP-1),
                  neutrophil collagenase (MMP-8),
                  collagenase-3 (MMP-13),
                  stromelysin-1 (MMP-3),
                  stromelysin-2 (MMP-10),
                  stromelysin-3 (MMP-11),
                  metalloelastase (MMP-12), MMP-19,
                  enamelysin (MMP-20), gelatinase A
                  (MMP-2), gelatinase B (MMP-9),
                  MT1-MMP (MMP-14), MT2-MMP
                  (MMP-15), MT3-MMP (MMP-16),
                  MT4-MMP (MMP-17) (ii) Plasminogen
                  activators (PAs)

Angiogenesis      Vascular endothelial growth factor
inducers          family (VEGF-A or VEGF, P1GF,
                  VGGF-B, VEGF-C, VEGF-D, orf virus
                  VEGF or VEGF-E), fibroblast growth
                  factor family (aFGF, bFGF, etc.),
                  angiopoietin 1 (Ang-1),
                  transforming growth factor-
                  alpha/beta (TGF [alpha]/[beta]),
                  platelet-derived growth factor
                  (PDGF), hepatocyte growth
                  factor/scatter factor (HGF/SF),
                  tumor necrosis factor-alpha
                  (TNF[alpha]), interleukin-1/8,
                  angiogenin, ephrins, integrins
                  [[alpha].sub.v][[beta].sub.3],
                  [[alpha].sub.v][[beta].sub.5],
                  [[alpha].sub.5][[beta].sub.1]
                  cyclooxygenase-2 (COX-2)

Angiogenesis      Thrombospondin-1/2 (TSP-1/2),
inhibitors        angiostatin (plasminogen
                  fragment), endostatin (collagen
                  XVIII fragment), vasostatin
                  (calreticulin fragment),
                  tumstatin, platelet factor-4
                  (PF4), antiangiogenic antithrombin
                  III, kringle 5 (plasminogen
                  fragment), prolactin 16-kD
                  fragment, fragment of SPARC,
                  2-methoxyestradiol,
                  metalloproteinase inhibitors
                  (TIMPs), interferon-alpha-beta-
                  gamma (IFN [alpha]-[beta]-
                  [gamma]), interleukin-12 (IL-12),
                  IP-10, Ang-2

Category          Major functions                        References

Proteolytic       MMPs; taking different substrates        [67-69]
enzymes           according to MMPs; substrates can
                  be collagen, gelatin, laminin,
                  fibronectin, proteoglycans, and
                  proMMPs

Angiogenesis      (i) Induction of EC proliferation,    [8-10, 70-79]
inducers          migration, and differentiation
                  (ii) TGF-[beta] shows opposite
                  effect in some contexts

Angiogenesis      (i) Inhibit EC proliferation/        11 15 18 80 85
inhibitors        migration
                  (ii) Induce EC apoptosis
                  (iii) TIMPs: inhibit MMP or uPA
                  activity
                  (iv) Ang-2: inhibit blood vessels
                  maturation, antagonist of Ang-1

TABLE 2: Clinical manipulation of angiogenesis.

Therapeutic       Diseases             Definitions-symptoms
goal

                  Hemangiomas          Benign and usually a self-
                                       involuting tumor (swelling or
                                       growth) of the endothelial
                                       cells that line blood vessels
                                       and is characterised by
                                       increased number ofnormal or
                                       abnormal vessels filled with
                                       blood

                  Psoriasis            Immune-mediated disease that
                                       affects the skin. The immune
                                       system mistakes a normal skin
                                       cell for a pathogen and sends
                                       out faulty signals that cause
                                       overproduction of new skin
                                       cells

                  Kaposi's sarcoma     Tumor caused by human
                                       herpesvirus 8 (HHV8)

                  Ocular               Abnormal or excessive formation
                  neovascularization   of blood vessels in the eye

Inhibition of     Rheumatoid           Inflammatory response of the
angiogenesis      arthritis            capsule around the joints
                                       (synovium), secondary to
                                       swelling (hyperplasia) of
                                       synovial cells, excess synovial
                                       fluid, and the development of
                                       fibrous tissue (pannus) in the
                                       synovium

                  Endometriosis        A gynecological medical
                                       condition in which cells from
                                       the lining of the uterus
                                       (endometrium) appear and
                                       flourish outside the uterine
                                       cavity, most commonly on the

                                       membrane which lines the
                                       abdominal cavity

                  Atherosclerosis      Artery wall thickens caused
                                       largely by the accumulation of
                                       macrophage white blood cells
                                       and promoted by low-density
                                       lipoproteins (LDL, plasma
                                       proteins that carry cholesterol
                                       and triglycerides)

                  Tumor growth and     Tumor-associated
                  metastasis           neovascularization is involved
                                       in tumor growth, invasion, and
                                       metastasis

Stimulation of    Induction of         After blood vessels blockage
angiogenesis      collateral vesse     (occulsion), collateral vessels
                  formation:           can be developed to improve
                  Myocardial           blood supply to the area.
                  ischemia,
                  Peripheral
                  ischemia,
                  Cerebral ischemia

                  Wound healing        Intricate process in which the
                                       skin (or another organ-tissue)
                                       repairs itself after injury.
                                       Angiogenesis occurs
                                       concurrently with fibroblast
                                       proliferation when endothelial
                                       cells migrate to the area of
                                       the wound

                  Reconstructive       Surgery to restore the form and
                  surgery              function ofthe body

Therapeutic       Diseases             Reference
goal

                  Hemangiomas             [86]

                  Psoriasis               [37]

                  Kaposi's sarcoma        [87]

                  Ocular                  [88]
                  neovascularization

Inhibition of     Rheumatoid              [36]
angiogenesis      arthritis

                  Endometriosis           [89]

                  Atherosclerosis         [35]

                  Tumor growth and        [4]
                  metastasis

Stimulation of    Induction of            [90]
angiogenesis      collateral vesse
                  formation:
                  Myocardial
                  ischemia,
                  Peripheral
                  ischemia,
                  Cerebral ischemia

                  Wound healing           [91]

                  Reconstructive
                  surgery

TABLE 3: Antiangiogenic compounds and their mechanism of action
(adapted from references [2, 92-102]).

Inhibiting        Antiangiogenic compounds   Mechanism ofaction
angiogenic
process

Inhibitors of     Batimastat, Marimastat,    MMP inhibitors, block
ECM remodeling    AG3340, Neovastat, PEX,    endothelial and tumor
                  TIMP-1,2,3,4               cell invasion

                  PAI-1,2, uPA Ab, uPAR Ab,  uPA inhibitors, block ECM
                  Amiloride                  breakdown

                  Minocycline,               Collagenase inhibitors,
                  tetracyclines, cartilage-  disrupt collagen
                  derived TIMP               synthesis and deposition

Inhibitors of     [[alpha].sub.v]            Block EC adhesion, induce
adhesion          [[beta].sub.3] Ab: LM609   EC apoptosis
molecules         and Vitaxin, RGD
                  containing peptides,
                  [[alpha].sub.v]
                  [[beta].sub.5] Ab

                  Benzodiazepine             Antagonist of
                  derivatives                [[alpha].sub.v]
                                             [[beta].sub.3]

Inhibitors of     Endogenous inhibitors:     Block EC proliferation,
activated ECs     endostatin, angiostatin,   induce EC apoptosis,
                  aaAT                       inhibit angiogenic switch

                  IFN-[alpha], IFN-          Block EC migration and/
                  [gamma],IL-12,             or proliferation
                  nitricoxide synthase
                  inhibitors, TSP-1

                  TNP 470, Combretastatin A  Block EC proliferation
                  4

                  Thalidomide                Inhibits angiogenesis in
                                             vivo

                  Linomide                   Inhibits EC migration

Inhibitors of     IFN-[alpha], PF-4,         Inhibit bFGF, Inhibit
angiogenic        prolactin fragment         bFGF-induced EC
                                             proliferation

inducers or       Suramin and analogues      Bind to various growth
their receptors                              factors including bFGF,
                                             VEGF, PDGF, inhibit EC
                                             migration and
                                             proliferation

                  PPS, distamycin A          Inhibit bFGF activity
                  analogues, bFGF Ab,
                  antisense-bFGF

                  Protamine                  Binds heparin, inhibits
                                             EC migration and
                                             proliferation

                  SU5416, soluble Flt-1,     Block VEGF activity
                  dominant-negative Flk-1,
                  VEGF receptor, ribozymes,
                  VEGF Ab

                  Aspirin, NS-398            COX inhibitors

                  6AT, 6A5BU, 7-DX           TP antagonists

Inhibitors of EC  Genistein                  Tyrosine kinase
intracellular                                inhibitor, blocks uPA, EC
signaling                                    migration and
                                             proliferation

                  Lavendustin A              Selective inhibitor of
                                             protein tyrosine kinase

                  Ang-2                      Inhibits Tie-2

Table 4: Selected angiogenesis inhibitors in clinical trials.

Inhibiting target        Drug             Sponsor

Epidermal growth       Gefitinib        AstraZeneca
factor receptor        (Iressa)          and Teva
(EGFR)

                       Lapatinib            GSK
                       (Tykerb)

                       Erlotinib       Genentech/OSI
                       (Tarceva)     pharmaceuticals/
                                           Roche

                      Canertinib     Selleck Chemicals
                       (CI-1033)

VEGFR                  Vatalanib      Bayer Schering
                      (PTK787 or       and Novartis
                        PTK/ZK)

VEGFR-2                IMC-1C11       ImClone Systems

VEGFR-3                mF4-31C1       ImClone Systems

Multiple growth facto  Imatinib          Novartis
factor receptors       (Glivec)

                       Sunitinib          Pfizer
                       (Sutent)

                      Sorafenib       Bayer and Onyx
                       (Nexavar)      pharmaceuticals

                       Pazopanib      GlaxoSmithKline
                      (Votrient)

VEGF                  Bevacizumab     Genentech/Roche
                       (Avastin)

Integrin                Vitaxin      Applied molecular
[[alpha].sub.v]                          evolution
[[beta].sub.3]

Inhibiting target        Drug        Clinical trials/mechanism

Epidermal growth       Gefitinib     FDA/approved in 2003 for NSCLC/
factor receptor        (Iressa)      effective in cancers with mutated
(EGFR)                               and overactive EGFR

                       Lapatinib     FDA/approved in 2007 for breast
                       (Tykerb)      cancer/dual tyrosine kinase
                                     inhibitor which interrupts the
                                     HER2/neu and epidermal growth
                                     factor receptor (EGFR) pathways

                       Erlotinib     FDA/approved in 2005/used to
                       (Tarceva)     treat nonsmall cell lung cancer,
                                     pancreatic cancer, and several
                                     other types ofcancer

                      Canertinib     Phase II-irreversible tyrosine-
                       (CI-1033)     kinase inhibitor with activity
                                     against EGFR, HER-2, and ErbB-4

VEGFR                  Vatalanib     Phase III-it inhibits all known
                      (PTK787 or     VEGF receptors, as well as
                        PTK/ZK)      platelet-derived growth factor
                                     receptor-beta and c-kit, but is
                                     most selective for VEGFR-2

VEGFR-2                IMC-1C11      Phase I/chimerized monoclonal
                                     antibody

VEGFR-3                mF4-31C1      Phase I-rat monoclonal antibody
                                     to murine VEGFR-3, which potently
                                     antagonizes the binding of VEGF-
                                     C to VEGFR-3

Multiple growth facto  Imatinib      FDA-approved in 2001-competitive
factor receptors       (Glivec)      tyrosine-kinase inhibitor used in
                                     the treatment of multiple
                                     cancers, most notably
                                     Philadelphia chromosome-positive
                                     (Ph+) chronic myelogenous
                                     leukemia (CML)

                       Sunitinib     FDA-approved in 2006 for renal
                       (Sutent)      cell carcinoma (RCC) and
                                     imatinib-resistant
                                     gastrointestinal stromal tumor
                                     (GIST)-the simultaneous
                                     inhibition of receptors for
                                     platelet-derived growth factor
                                     (PDGF-Rs) and vascular
                                     endothelial growth factor
                                     receptors (VEGFRs)

                      Sorafenib      FDA-approved in 2005-a small
                       (Nexavar)     molecular inhibitor of several
                                     tyrosine protein kinases (VEGFR
                                     and PDGFR) and Raf kinases (more
                                     avidly C-Raf than B-Raf)

                       Pazopanib     FDA-approved in 2009 for advanced
                      (Votrient)     renal cancer-multitargeted
                                     receptor tyrosine kinase
                                     inhibitor of VEGFR-1, VEGFR-2,
                                     VEGFR-3, PDGFR-a-[beta], and c-
                                     kit

VEGF                  Bevacizumab    FDA-approved in 2004 for
                       (Avastin)     metastatic colorectal cancer-
                                     humanized anti-VEGF mAb, licensed
                                     to treat various cancers
                                     including colorectal, lung,
                                     breast (outside the USA),
                                     glioblastoma (USA only), kidney,
                                     and ovarian

Integrin                Vitaxin      Phase II as a treatment for
[[alpha].sub.v]                      colorectal cancer/humanized
[[beta].sub.3]                       monoclonal antibody against the
                                     vascular integrin [[alpha].sub.v]
                                     [[beta].sub.3]

Inhibiting target        Drug        References

Epidermal growth       Gefitinib     [103 104]
factor receptor        (Iressa)
(EGFR)

                       Lapatinib       [105]
                       (Tykerb)

                       Erlotinib       [106]
                       (Tarceva)

                      Canertinib       [107]
                       (CI-1033)

VEGFR                  Vatalanib       [108]
                      (PTK787 or
                        PTK/ZK)

VEGFR-2                IMC-1C11        [109]

VEGFR-3                mF4-31C1        [110]

Multiple growth facto  Imatinib        [111]
factor receptors       (Glivec)

                       Sunitinib       [112]
                       (Sutent)

                      Sorafenib
                       (Nexavar)     [113 114]

                       Pazopanib
                      (Votrient)

VEGF                  Bevacizumab
                       (Avastin)
                                     [115 116]

Integrin                Vitaxin        [117]
[[alpha].sub.v]
[[beta].sub.3]
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Author:Yoo, So Young; Kwon, Sang Mo
Publication:Mediators of Inflammation
Article Type:Report
Date:Jan 1, 2013
Words:8103
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