Angiogenesis as a target for cancer therapy

Hematol Oncol Clin N Am 16 (2002) 1125 – 1171

Angiogenesis as a target for cancer therapy Kerim Kaban, MD, Roy S. Herbst, MD, PhD* Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Angiogenesis, or the formation of new blood vessels, is essential for normal reproduction, development, and repair. In adults, physiologic angiogenesis lasts for only days or weeks and is otherwise suppressed, such that, endothelial cells have turnover times of hundreds of days [1]. Stimuli such as hypoxia, however, can tip the net balance between proangiogenic and antiangiogenic factors that normally keep physiologic angiogenesis under tight control, and this turns on the angiogenic ‘‘switch’’ (Fig. 1) [2]. In 1971, Folkman proposed that tumor growth depends on angiogenesis and that tumors might activate resting endothelial cells to proliferate by secreting a ‘‘diffusible’’ chemical signal [3]. Although Folkman’s hypothesis was not accepted widely initially, over the following 31 years, direct and indirect evidence was obtained showing that, indeed most tumors must induce angiogenesis to grow beyond a few millimeters [4]. Endothelial cells are recruited by tumors to produce growth and survival factors for tumor cells [5] and to initiate the formation of new blood vessels, thus forming a paracrine feedback loop (Fig. 2). Without angiogenesis, primary tumors or metastases cannot develop into clinically significant disease [6]. The combined necessity for tumors to create new blood vessels to grow and the restriction of normal angiogenesis in healthy adults to only a few short-lasting situations therefore provide a very selective target for antiangiogenic cancer therapies (Fig. 3). Targeting angiogenesis is also an attractive strategy, because vascular endothelial cells are genetically stable and less likely to develop resistance to therapy than neoplastic cells in their vicinity [7]. Moreover, unlike cancer cells, which are unique to each disease and require tailored therapy, the tumor endothelium is a relatively uniform and normal cell type. Therefore, it is

* Corresponding author. E-mail address: [email protected] (R.S. Herbst). 0889-8588/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 8 9 - 8 5 8 8 ( 0 2 ) 0 0 0 4 7 - 3

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Fig. 1. The balance hypothesis for the angiogenic switch. Abbreviations: FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor (From Hanahan D, Folkman J. Cell 1996;86:353 – 64.)

reasoned that antiangiogenic therapy might be effective against a broad range of tumor types in most cases.

Physiology of angiogenesis Overview Angiogenesis involves a cascade of events, in which mature and resting endothelial cells are stimulated to proliferate, degrade their basement membranes, migrate, and form new blood vessels (Fig. 4). In response to angiogenic stimuli such as vascular endothelial growth factor and fibroblast growth factor, endothelial cells first proliferate and degrade their basement membranes. A family of protease enzymes, matrix metalloproteinases are essential for this process [8]. The endothelial cells then develop sprouts and migrate toward the surrounding stroma, a process mediated by vascular cell adhesion molecules such as integrins avb3 and a5 [9]. In the next steps, endothelial cells form tubes

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Fig. 2. The paracrine loop of growth and survival factors between endothelial and tumor cells. Abbreviations: BM, basement membrane; EC, endothelial cell; FGF, fibroblast growth factor; IL-8, interleukin 8; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Fig. 3. Major differences between antiangiogenic and cytotoxic therapy.

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#

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Fig. 4. The angiogenic cascade and major mediators of angiogenesis. , stimulates; , inhibits. Abbreviations: Ang, angiopoietin; FGF, fibroblast growth factor; IFN, interferon; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TIMP, tissue inhibitor of matrix metalloproteinase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

and become capable of handling blood flow. Playing an important role in this maturation step are angiopoietin-1 (Ang1), which recruits smooth muscle cells and pericytes; and ephrins, which promote fusion of the newly formed endothelial tubes. Ephrins also have functions in other processes, including cell adhesion and migration [10]. To design specific therapy, it is important to understand the differences between tumor and physiologic angiogenesis. For example, in tumors, Ang1, the vessel stabilizer of angiogenesis, is blocked by angiopoietin-2 (Ang2) produced by endothelial cells in the tumor bed. As a result, pericytes and smooth muscle cells are repelled, and the newly formed vessels are thin-walled and leaky because of the unopposed effects of vascular endothelial growth factor [11]. Therefore, vascular endothelial growth factor, working with Ang2, plays an essential role in tumor angiogenesis. In physiologic angiogenesis, such as in wound healing, overexpression of vascular endothelial growth factor is balanced by Ang1 [12,13]. Lymphatic-specific vascular endothelial growth factors (VEGF-C and VEGF-D) and receptors (VEGFR-3) also have been identified, and lymphatic angiogenesis may become a new target for cancer research and therapy in the near future [14].

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Turning the angiogenic ‘‘switch’’ on or off The balance hypothesis Under physiologic and abnormal conditions, the development of sprouting angiogenesis appears to depend on the net balance of negative and positive regulators of angiogenesis at the local tissue level (see Fig. 1) [15,16]. Many tumors secrete unusually high levels of proangiogenic factors such as vascular endothelial growth factor and fibroblast growth factor to recruit endothelial cells from mature blood vessels in their vicinity and to promote the formation of new blood vessels [17 –20]. There are at least 15 endogenous proangiogenic factors involved in tumor angiogenesis, and most are secreted by tumor cells [15]. It also has been shown repeatedly that tumors produce systemically active antiangiogenic factors such as endostatin, angiostatin, or thrombospondin-1 (TSP-1). Interestingly, these factors might suppress the growth of distant metastatic tumors but not the primary tumor [21 –23]. The cellular machinery involved in apoptosis, among other factors, plays a paramount role in the integration of positive and negative angiogenic signals. Inducers of angiogenesis can serve as survival factors for endothelial cells [24] and stimulate the production of antiapoptotic molecules [25,26]. In turn, many inhibitors of angiogenesis are proapoptotic [27,28]. Thus, the apoptotic machinery may serve as a ‘‘fulcrum’’ on which cells ‘‘balance’’ the inhibitors and stimulators of angiogenesis [28]. Therefore, when the level of stimulators of angiogenesis exceeds the level of inhibitors at any local tissue level, the endothelial cells ‘‘decide’’ to commit to angiogenesis. For example, for a primary tumor secreting positive and negative regulators of angiogenesis, the primary tumor may grow where the balance favors angiogenesis, while the growth of metastatic tumors may be suppressed, where the balance favors the suppression of angiogenesis far away from the primary tumor [21,22]. Hypoxia, transforming growth factor-b, and von Hippel-Lindau tumor suppressor protein Hypoxia induces the vascular endothelial growth factor paracrine system by increasing the transcription of vascular endothelial growth factor and its receptor, VEGFR-1 (Flt-1) and by stabilizing vascular endothelial growth factor mRNA (Fig. 5). The hypoxia-inducible transcription factor 1 (HIF-1) complex mediates these effects [29]. An important regulator of this complex is the von Hippel-Lindau tumor suppressor protein, which serves as a cellular oxygen sensor [30]. In the presence of oxygen, HIF-1a binds to von Hippel-Lindau protein. This leads to the rapid degradation of HIF-1a and the ensuing downregulation of vascular endothelial growth factor transcription [31]. Von Hippel-Lindau gene activity is lost in some sporadic cases of renal cell carcinoma and in the tumors of patients with von Hippel-Lindau syndrome. This leads to the deregulated expression of vascular endothelial growth factor even under normoxic conditions, emphasizing the importance of von Hippel-

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Fig. 5. Hypoxia and the angiogenic ‘‘switch.’’ Abbreviations: Flt-1, vascular endothelial growth factor receptor 1; HIF, hypoxia-inducible transcription factor; NSAID, non-steroidal antiinflammatory drug; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau gene product.

Lindau protein in the oxygen-dependent regulation of vascular endothelial growth factor expression [32]. Another growth factor, transforming growth factor b (TGF-b), synergistically cooperates with hypoxia in the induction of the promoter activity of vascular endothelial growth factor (Fig. 5) [33]. Accordingly, the hypoxia-related increase in vascular endothelial growth factor expression is even more significant in the presence of TGF-b [34]. It is, however, important to note that increased expression of vascular endothelial growth factor alone is not enough to induce angiogenesis. Its receptors must be expressed, too. Selected endogenous stimulators of angiogenesis Vascular endothelial growth factor The vascular endothelial growth factor family of ligands are the key regulators of angiogenesis and lymphangiogenesis and include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (Fig. 6). In addition, VEGF-A, which is usually referred to as just vascular endothelial growth factor, has five different isoforms named on the basis of the number of amino acids they possess. VEGF165

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Fig. 6. VEGF family of ligands and receptors, and their functions. VEGFR-1 is believed to be a decoy receptor, avidly binding and trapping VEGF (VEGF-A), a key regulator of angiogenesis. VEGFR-2 and -3 are the principal receptors responsible for promoting VEGF-mediated angiogenesis and lymphangiogenesis, respectively. VEGF-C and -D can to bind both of these receptors, and as a result, they have angiogenic and lymphangiogenic effects. Neuropilin-1 (NRP-1) potentiates VEGF binding to VEGFR-2. Abbreviations: NRP, neuropilin; PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. (Modified from Karkkainen MJ, Makinen T, Alitalo K. Nat Cell Bio 2002;4:E2 – 5.)

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is the predominant type produced by many normal and neoplastic cells. VEGF121, 145, 189 and VEGF206 are the other four isoforms [35]. Vascular endothelial growth factor is produced by a variety of cell types, including tumor cells. It is an endothelial cell mitogen, mediator of vascular permeability (also called vascular permeability factor), a key survival factor for endothelial cells in immature blood vessels, and an inducer of endothelial cell migration (Table 1) [24]. Vascular endothelial growth factor plays a paramount role in embryonic vasculogenesis, and the loss of even a single vascular endothelial growth factor allele is lethal in the mouse embryo, since it results in impaired angiogenesis and blood-island formation [36,37]. Although vascular endothelial growth factor is essential for endothelial cell survival in immature vessels and in development, once maturation is reached, vascular endothelial growth factor dependence is lost [38]. Vascular endothelial growth factor binds to two different tyrosine kinase receptors on endothelial cells (Fig. 6): VEGFR-1 (Flt-1) [39] and VEGFR-2 (also known as Flk-1 in mice and KDR in humans) [40]. VEGFR-2 is the primary receptor promoting the angiogenic effects of vascular endothelial growth factor [41]. VEGFR-1 on adult endothelial cells, on the other hand, is believed to be a high-affinity ‘‘decoy receptor’’ negatively regulating the activity of vascular endothelial growth factor by making it less available to VEGFR-2 [42]. On other cell types, VEGFR-1 may have other functions such as mediating monocyte chemotaxis [43] or inducing matrix metalloproteinase expression by smooth muscle cells [44]. An interesting study in mice suggested that VEGFR-1 and its ligand placental growth factor promotes hematopoiesis. In that study, placental growth factor shortened the extent and duration of neutropenia after chemotherapy, and inhibition of VEGFR-1 signaling blocked hematopoietic recovery. By inducing the motility and

Table 1 Selected mediators of vascular endothelial growth factor effects Induced by vascular endothelial growth factor

End result

p42/p44 (but inhibits p38) CCDPK signaling [25]

Prevents TNF-a- & H2O2-induced endothelial cell apoptosis Prevents endothelial cell apoptosis Matrix and basal membrane degradation leading to cell mobilization Suppression of Tie2 signal (required for the initiation of VEGF induced angiogenesis) Increased permeability

Bcl-2 [26] Matrix metalloproteinases from supporting cells [44,45] Conversion of the Tie2:Tie1 complex to full-length-Tie2 and Tie1-endodomain [46] Activation of the PI-3 kinase, PKB, NOS, and MAP-kinase signaling cascades [47] ICAM-1 [48] MCP-1, chemokine receptor CXCR4, & IL-8 [49]

Increased leukocyte adhesion Leukocyte infiltration

Abbreviations: CCDPK, calcium-calmodulin dependent protein kinase; ICAM-1, intracellular adhesion molecule; IL-8, interleukin-8; MAP, mitogen-activated protein; MCP-1, monocyte chemo-attractant protein-1; NOS, nitric oxide synthase; PI, phosphatidylinositol; PKB, protein kinase B; TNF, Tumor necrosis factor.

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migration of hematopoietic stem cells, placental growth factor presumably promoted their entry into a permissive environment, essential for cell cycling and mobilization [45]. A recently identified vascular endothelial growth factor receptor, neuropilin-1 (NRP-1), forms a ternary complex with VEGFR-2 and VEGF165 (but not VEGFR121) and potentiates its effects (Fig. 6). NRP-1 is expressed on endothelial cells, tumor cells, and neurons, where it was previously recognized to be a receptor for neuronal guidance mediators. The presence of NRP-1 on tumor cells is important because of its ability to form juxtacrine associations with the VEGFR-2 of neighboring endothelial cells, which enhances VEGF165 binding [50]. Consistent with this, overexpression of NRP-1 in rat prostate cancer leads to a significant increase in tumor angiogenesis and growth [51]. In addition to their role in angiogenesis, VEGF-C and VEGF-D are believed to play an important role in tumor lymphangiogenesis and the spread of tumor cells through lymphatics [52 –55]. Consistent with this dual role, they bind to both VEGRF-2 and VEGFR-3, and the latter is located exclusively on lymphatic endothelial cells (Fig. 6). The function of VEGF-B is less clear, but it is believed to be involved in coronary vascularization and growth [56]. A number of factors modulate the expression of vascular endothelial growth factor and its receptors and thereby affect angiogenesis (Tables 2 and 3). One interesting finding is nicotine’s ability to stimulate tumor angiogenesis by increasing vascular endothelial growth factor expression on endothelial cells [57]

Table 2 Factors up-regulating vascular endothelial growth factor and/or vascular endothelial growth factor receptor expressions Factor

Mechanism

Hypoxia [58,59]

HIF-mediated increased transcription & stabilization of vascular endothelial growth factor mRNA Increased TGF-b1 Cooperates with HIF in inducting promoter activity of vascular endothelial growth factor gene Unknown (at concentrations usual in habitual smokers) Transforms endothelial cells; up-regulates vascular endothelial growth factor, VEGF-C, VEGF-D and their receptors Direct induction of vascular endothelial growth factor gene by estrogen receptor Mediated through p38 MAP kinase activation Unknown (in ovarian cancer)

Ras transformation [60] TGF-b1 [60]

Nicotine and cotinine [57] Human herpes virus-8 [61]

Estrogen [62] 1,25-Dihydroxyvitamin D3 [63] FSH and LH [64]

Abbreviations: FSH, follicle-stimulating hormone; HIF, hypoxia-inducible transcription factor; LH, luteinizing hormone; MAP, mitogen-activated protein; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

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Table 3 Factors down-regulating or attenuating vascular endothelial growth factor and/or vascular endothelial growth factor receptor activity Factor

Mechanism

TNF-a [65]

SHP-1-mediated inactivation of vascular endothelial growth factor receptor tyrosine kinase Down-regulates vascular endothelial growth factor/VEGFR-1 transcription through proteolysis of HIF-1a Inhibits VEGF-induced angiogenesis by binding to vascular endothelial growth factor Acting through D2 receptors, causes endocytosis of VEGFR-2 Increased turnover of vascular endothelial growth factor mRNA Inhibit vascular endothelial growth factor receptor phosphorylation

von Hippel-Lindau protein [66]

Connective tissue growth factor [67] Dopamine [68] Glucocorticoids [69] Green tea catechins [70]

Abbreviations: HIF, hypoxia-inducible transcription factor; SHP-1, src homology 2-containing protein-tyrosine phosphatase 1; TNF, tumor necrosis factor; VEGFR, vascular endothelial growth factor receptor

and through acetylcholine receptors [71], which underscores the importance of smoking cessation at any time, before or after the diagnosis of a cancer. Angiopoietins Vascular endothelial growth factor is essential for early angiogenesis, but it has to work in concert with other factors to create healthy blood vessels. The unregulated expression of vascular endothelial growth factor creates leaky and hemorrhagic blood vessels. Angiopoietins are among the most important partners of vascular endothelial growth factor in ensuring the formation of healthy blood vessels [72]. There are three known angiopoietins in humans: Ang1, Ang2, and Ang4; all three are ligands for the Tie2 tyrosine kinase receptor. Ang1 and Ang4 are activators of Tie2, and Ang2 is an antagonist [73]. The binding of Ang1 to Tie2 induces endothelial cells to recruit and incorporate pericytes and smooth muscle cells into the vessel wall, which is mediated by platelet-derived growth factor [74]. Produced by endothelial cells, Ang1 plays a very important role in the remodeling and stabilization of the immature network of blood vessels formed under the effect of vascular endothelial growth factor. There is evidence that it works by facilitating the integration of endothelial cells with supporting cells, which allows them to receive critical signals from their environment [75]. In its absence, networks of mature blood vessels do not form [76], and its presence makes vessels leak resistant [72]. In fact, Ang1 may be the only known agent that can make vessels leak-resistant, whether the leakage is induced by vascular endothelial growth factor or inflammatory agents.

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In contrast, Ang2, a Tie2 antagonist, is believed to destabilize existing vessels, permitting remodeling in the presence of vascular endothelial growth factor and vessel regression in its absence. In line with this, Ang2 is expressed at sites of remodeling, such as in the female reproductive tract and during tumor growth, whereas Ang1, which stabilizes blood vessels, is expressed constitutively in the adult [11,77]. This critical balance among Ang1, Ang2, and vascular endothelial growth factor also may be essential in determining the type of tumor angiogenesis that starts with vessel co-option, in which the tumor initially grows by internalizing existing host vessels. Initially the co-opted vasculature regresses, leading to massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin [77]. Another factor possibly involved in angiogenesis is Tie1. It is an orphan tyrosine kinase receptor expressed predominantly on endothelial cells and some hematopoietic progenitor cells [78]. Tie1 is required for normal embryonic vascular development [79]. Tie1 expression is increased in angiogenesis and hypoxia, and vascular endothelial growth factor independently appears to contribute to its up-regulation through a transcription-dependent mechanism [80]. Tie1’s ligands are not known, and its function in the adult is not understood fully; however, there is evidence that vascular endothelial growth factor’s effects on endothelial cell proliferation and increased vascular permeability may be mediated at least partly by Tie1. Vascular endothelial growth factor and the inflammatory cytokines tumor necrosis factor -a (TNF-a) and interleukin-1b (IL-1b) mediate the cleavage of the extracellular part of Tie1 through a metalloproteinase. Blocking this cleavage inhibits vascular endothelial growth factor-induced (but not fibroblast growth factor-2-induced) endothelial cell proliferation [81]. Tie1 may also have a role in preventing endothelial cell apoptosis by activating phosphatidylinositol 3-kinase and Akt [82].

Fibroblast growth factors Fibroblast growth factor-2 (FGF-2, also known as basic fibroblast growth factor, or bFGF) was the first angiogenic factor identified, followed shortly by FGF-1 (also known as acidic or aFGF) [83]. As many as 20 fibroblast growth factors have been identified. Fibroblast growth factors are produced by many different cells, including tumor cells and endothelial cells in the tumor vasculature [84 – 87]. Other cell types such as macrophages or mast cells also might be recruited by tumors to increase their secretion of fibroblast growth factor [87,88]. FGF-1 and -2 are potent angiogenic molecules and stimulate endothelial cell mitosis, migration [89], morphogenesis [90], and survival [19,91], but they lack the specificity of vascular endothelial growth factor. For example, FGF-2 has many targets other than endothelial cells, including fibroblasts, smooth muscle cells, and neurons. It plays an important role in the development and/or function of the nervous system, eyes, and skeleton, among many other organ systems [92].

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Fibroblast growth factors bind to heparan sulfate proteoglycans, which are located on the surface of most cells or within the extracellular matrix. This serves as a reserve supply of fibroblast growth factors in the extracellular matrix, allowing them to be released when necessary [93,94]. In addition, heparin sulfate proteoglycans stabilize and increase the affinity of fibroblast growth factors for the tyrosine kinase receptors they bind to: fibroblast growth factor receptor-1 (FGFR-1) through FGFR-4 [95]. Whereas the overexpression of FGF-2 and its receptors has been implicated in malignant transformation and progression [96], this induces tumor cell death in certain tumors. In Ewing’s sarcoma, for example, FGF-2 induces cell death, in vitro and in vivo [97]. Fibroblast growth factor-induced cell growth inhibition also was observed in breast cancer and medulloblastoma cell lines [98,99]. This is apparently because of the accumulation of cells at the G1 checkpoint [100]. Matrix metalloproteinases Matrix metalloproteinases are endopeptidases that degrade various protein components of the extracellular matrix and basal membranes [101]. These enzymes comprise four main subfamilies: collagenases, gelatinases, stromelysins, and membrane-bound matrix metalloproteinases [102]. Matrix metalloproteinase expression is increased around malignant tumors, and this is frequently a marker of poor prognosis, alone or with other prognostic markers [20,101,103,104]. In epithelial cancers, most matrix metalloproteinases are overexpressed by the supporting stromal cells, but this often is induced and controlled by the malignant cells. Indeed, highly malignant cells are made less aggressive when their matrix metalloproteinase activity is suppressed, whereas relatively benign cells acquire malignant properties when the activity of matrix metalloproteinases is increased or the activity of tissue inhibitors of matrix metalloproteinases is decreased [101]. In addition, matrix metalloproteinases, especially matrix metalloproteinase-2 (MMP-2), are required to switch on the angiogenic phenotype [105]. On the basis of evidence suggesting that matrix metalloproteinases are essential for cancer invasion, metastasis, and angiogenesis, clinical trials of matrix metalloproteinase inhibitors were conducted. These agents failed to show any significant clinical efficacy in advanced cancer, however. In retrospect, this outcome might have been anticipated, since matrix metalloproteinases appear to be important early in cancer progression (local invasion and micrometastasis) and may not be required once metastases have been established [106]. Indeed, this was indicated in a phase III trial of marimastat (a matrix metalloproteinase inhibitor) monotherapy, in which the subgroup of patients without metastases particularly benefited from the drug [107]. Future trials in patients with earlier stages of cancer therefore might achieve better results. Other reasons for the lack of apparent clinical benefit might be a possible redundancy of the matrix metalloproteinase system and inadequate dosing resulting from the high frequency of adverse effects.

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Integrins Integrins are cell-surface receptors that anchor cells to the extracellular matrix and transduce signals from the extracellular environment to the cell’s interior [108]. Among the many different types of integrins expressed by endothelial cells, avb3 is especially important, because, though minimally expressed on resting vessels, it is up-regulated during angiogenesis [109]. In animal models, integrin antagonists were found to block angiogenesis induced by vascular endothelial growth factor, fibroblast growth factor, and tumors, with little adverse effects on pre-existing blood vessels [110– 112]. On the basis of such findings, vitaxin, an avb3 integrin antagonist, was developed for antiangiogenic treatment in humans and is in clinical trials. Cross talk between avb3 and vascular growth factor receptors is essential to coordinate, amplify, and fine tune angiogenesis [113]. For example, vascular endothelial growth factor up-regulates the expression and/or increases the activity of avb3, avb5 and other vascular integrins [114,115], whereas tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) selectively inhibit avb3 integrindependent cell adhesion and survival [116]. Although the inhibition of pathological angiogenesis by integrin antagonists suggested that they are essential for angiogenesis, in fact, studies in mice showed that angiogenesis was enhanced in mice deficient in integrins av, b3, b5, and b3/b5 [115,117]. These unexpected and contrasting effects from the genetic deficiency of integrins and integrin antagonists on pathological angiogenesis prompted a number of explanations [114,115]. One was that the integrins might be allowing vessels to form in the presence of certain ligands and inhibiting them in the absence of those same ligands. Integrin antagonists could mimic the unligated state and inhibit vessel growth, and the genetic absence of these integrins might eliminate the negative signals, thereby enhancing angiogenesis [115]. Ephrins and Eph receptors Ephrins are unique among receptor tyrosine kinase ligands in that they must be tethered to membranes to activate their receptors [118], and their interactions with Eph receptors activate signaling pathways in a bidirectional fashion through Eph receptors and ephrin ligands. The Eph receptors comprise the largest known family of tyrosine kinase receptors. They play critical roles in developmental and adult sprouting angiogenesis, mediating juxtacrine cell-to-cell contacts, adhesion to extracellular matrix, and migration [10]. These receptors are divided into two groups: EphA and EphB, binding ephrinA or ephrinB ligand groups, respectively. Each subgroup of Eph receptors can bind different ephrins from the same subgroup [10]. Many types of tumor cells and tumor-associated endothelial cells overexpress Eph receptors and ephrin ligands. Ephrin A1 and EphA2 ligand-receptor pairs are expressed consistently in a variety of tumor cells and endothelial cells, respectively [119]. How Eph/ephrin regulates tumor angiogenesis is not known, but ephrins on tumor cells might function as contact-dependent organizing molecules that guide incoming vessels expressing EphA2 receptor. Ephrins on endothelial

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cells also may interact with Eph receptors on adjacent endothelial cells, promoting sprouting angiogenesis, migration, and capillary tube formation through bidirectional signaling [10]. Selected endogenous inhibitors of angiogenesis Angiostatin Angiostatin is a circulating fragment of plasminogen that has profound inhibitory effects on angiogenesis. It is produced when enzymes, including matrix metalloproteinases [120], are released from various types of cells and cleave to circulating plasminogen [121]. Angiostatin was isolated initially from mice with subcutaneous Lewis lung carcinoma in which the primary tumors were suppressing the growth of metastases by inhibiting angiogenesis [21]. It subsequently was found that angiostatin induces endothelial cell apoptosis [27,122] and inhibits endothelial cell proliferation, [123] migration, [124] and capillary tube formation, probably through its inhibitory effects on the endostatin receptors ATP synthase [125], and angiomotin [126]. Bone marrow-derived endothelial cell precursors that have an important role in angiogenesis appear to be much more sensitive to the effects of angiostatin than mature endothelial cells. This suggests that the antiangiogenic effects of angiostatin might be mediated, at least partly, by inhibiting endothelial cell precursors [123]. Angiostatin-induced antiangiogenesis might be caused partly by its effects on leukocytes. Leukocytes may play an important role in certain types of angiogenesis by secreting angiogenic factors such as vascular endothelial growth factor [127] and by degrading the matrix and creating a cleft that is lined up with endothelial cells to form new blood vessels. Indeed, angiostatin has proven to be a strong inhibitor of neutrophil-induced angiogenesis in response to CXCR2 ligands, such as IL-8 [128]. Neutrophils, like endothelial cells, express the angiostatin receptor ATP synthase on cell membranes and the mRNA of angiomotin [128], and angiostatin is believed to inhibit neutrophil-mediated angiogenesis by interfering with cell-surface ATP metabolism [129]. Endostatin Endostatin, a C-terminal fragment of collagen XVIII, is a potent endogenous inhibitor of endothelial cell proliferation and migration [22,130]. It is produced when the collagen XVIII, abundant in vascular basement membranes [131], is cleaved by various proteolytic enzymes, including cathepsin L, elastase, and matrix metalloproteinases [132]. Endostatin was identified originally as a tumor product inhibiting the growth of metastases. Administration of endostatin in mice led to regression of primary tumors to dormant microscopic lesions with balanced proliferation and apoptosis and inhibition of angiogenesis [22]. Endostatin exerts its antiangiogenic effect through various pathways. It induces endothelial cell-cycle arrest at the G1 phase by inhibiting cyclin D1 [133]. Additionally, it promotes endothelial cell apoptosis mediated by tyrosine kinase signaling through the Shb adaptor protein [134]. The interaction of

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endostatin with tropomyosin-associated microfilaments in endothelial cells and subsequent disruption of microfilament integrity has been proposed as a mechanism by which it inhibits cell motility, induces apoptosis, and ultimately inhibits tumor growth [135]. In keeping with this, blockage of this interaction released most of the endostatin-induced tumor inhibition in the B16-BL6 metastatic melanoma model [135]. Endostatin was also found to inhibit the vascular endothelial growth factor-induced mobilization of bone marrow-derived endothelial progenitor cells, which could constitute a novel mechanism for endostatin’s antiangiogenic activity [137]. Although endostatin profoundly inhibits tumor angiogenesis, it has little effect on the physiologic angiogenesis of wound healing [137]. This was shown in endostatin-treated mice, in which the number of functional blood vessels and the matrix density in the granulation tissue were reduced, but the overall wound healing process was not affected significantly [138]. Exactly how endostatin has such a different effect on tumor and physiologic angiogenesis is not known, but it may have to do with different levels of regulatory factors. Endostatin expression may be dysregulated in some tumors. One mechanism of such dysregulation is the overexpression of ornithine decarboxylase by various cancers. Ornithine decarboxylase is believed to suppress collagen XVIII and endostatin expression, and its overexpression is associated with increased tumor growth and angiogenesis [139]. Thrombospondins Thrombospondins are a family of extracellular glycoproteins that participate in cell-to-cell and cell-to-matrix communications. There are five members of the thrombospondin family: TSP-1 to TSP-5. Of these, only TSP-1 and TSP-2 have antiangiogenic activity [140,141]. Thrombospondins are multifunctional molecules. For example, besides its antiangiogenic effects, TSP-1 participates in cell adhesion, motility, proliferation, and apoptosis; the modulation of protease activity; TGF-b activation; platelet aggregation; cytoskeletal organization; and neurite outgrowth. It also plays an important role in stromal organization and the proliferation of smooth muscle cells and fibroblasts [142]. Given their wide range of actions, it is easier to think of thrombospondins as multiple ligands, each with its own cell type and receptor specificity, organized in one molecule (Fig. 7). Moreover, the conformational flexibility of thrombospondins affects the availability of binding sites, which depends on the presence of other factors such as calcium in the medium. The biology of TSP-1 has been studied most extensively because of its abundance in platelet a granules. TSP-1 and -2 are composed of the same domains and have significant structural homology. Inducing the apoptosis of endothelial cells in newly forming vessels is one of the most important means by which TSP-1 inhibits angiogenesis [143]. It requires the transmembrane receptor CD36, and the downstream mediators p59fyn, caspases, and p38MAPK to activate the apoptotic machinery. This action of TSP-1 is limited mostly to activated or stressed endothelial cells [28]. Recently, it was shown that TSP-1

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Fig. 7. Thrombospondin 1 and its receptors. The TSP-1 peptide chain consists of (N- to C-terminal): (1) a heparin-binding domain (HBD) that binds to cell-surface proteoglycans and lipoprotein-receptorrelated protein (LRP), (2) a domain related to the N-terminal propeptide of collagens (PC) that is the collagen-binding domain of TSP-1, (3) three type 1 repeats that contain binding sites for a3b1 integrin and CD36, (4) three type 2 or epidermal growth factor (EGF)-like repeats thought to be responsible for the interaction of TSP-1 with soluble and matrix proteins, (5) a highly repetitive Ca2+-binding region that contains the single RGD sequence of TSP-1 that binds to integrins aIIbb3 and avb3, and (6) the C-terminal cell-binding domain (CBD) that contains the two VVM sequences that bind to integrinassociated protein (IAP/CD47). Note that the proximity of the RGD and VVM motifs might allow for simultaneous engagement of the beta3 integrin and CD47. (From Brown EJ, Frazier WA. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 2001;11:130 – 5; with permission.)

also can cause Fas-dependent apoptosis of endothelial cells by up-regulating the Fas ligand on endothelial cells. In this case, the essential receptor of Fas ligand, Fas/CD95, is expressed selectively on endothelial cells stimulated by angiogenic inducers as opposed to resting endothelial cells [144]. Because thrombospondins are expressed by many normal tissues, it is particularly important to induce apoptosis selectively in stimulated endothelial cells but not in endothelial cells at rest. The TSP-1 gene maps to 15q15 and loss of heterozygosity in chromosome 15 was observed in metastases of nonsmall cell lung cancer (56%) and of breast (70%) and colorectal (67%) carcinomas. In breast cancer, the difference in the loss of heterozygosity between nonmetastatic primary tumors and brain metastases was particularly significant (11% versus 70%) [145]. Similarly, metastasizing head and neck tumors showed a high frequency of chromosome 15q deletions [146]. In cell lines lacking an entire copy of chromosome 15, introduction of the chromosome had no effect on in vitro tumor cell proliferation, but in vivo, it had a significant tumor-suppressive effect. The fact that the TSP-1 gene maps to 15q15 suggests that it was instrumental in the tumor suppressive effect of the chromosome 15 that was reintroduced in the tumor cell

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lines. Indeed, when these tumor cell lines were transfected to express TSP-1, in vivo tumor growth was suppressed [147]. In human skin, TSP-1 is deposited in the basement membrane, where it contributes to the antiangiogenic barrier that separates the avascular epidermis from the vascularized dermis. TSP-1 expression is down-regulated in squamous cell carcinomas of the skin. Moreover, the growth of tumor xenografts was suppressed when the squamous cell carcinomas of skin cell lines were transfected to overexpress TSP-1. This inhibition of tumor growth apparently was caused by the antiangiogenic effects of TSP-1 and the microvessel density, and the number of large vessels were reduced in TSP-1-overexpressing tumors [148]. Similarly, transfection of squamous cell carcinomas of skin cell lines to overexpress TSP-2 strongly suppressed tumor growth and angiogenesis in nude mice [149]. In addition, in nude mice, xenografts of human melanoma overexpressing TSP-1 suppressed metastases [150]. Similarly, tumors generated by transfected breast cancer cells overexpressing TSP-1 were less likely to metastasize, had a lower microvessel density and a decreased growth rate compared with controls [151]. In another animal study, systemic treatment with TSP-1 peptide mimetics suppressed the growth of human melanoma metastasis but had no effect on tumor cells in vitro [152]. These studies demonstrated the antitumor effects of thrombospondins mediated by antiangiogenesis. Other studies, however, have shown that thrombospondin overexpression also may cause tumors to be more aggressive. For example, in one study, a human squamous cell carcinoma line with high TSP-1 expression and an invasive phenotype was transfected with a thrombospondin cDNA antisense expression vector. In athymic mice inoculated with the antisense clones, tumor growth either was suppressed completely or slowed, whereas tumors grew rapidly in control animals. Moreover, transfected clones generated highly differentiated tumors, whereas the tumors in control animals were invasive and poorly differentiated [153]. This high expression of thrombospondin in certain situations that made tumors more aggressive might be because of the complex nature of the thrombospondin-cell and thrombospondin-matrix interactions and supports the notion that thrombospondins may have different modulatory functions depending on local conditions.

Angiogenesis and cancer therapy A new paradigm for assessing drug efficacy: antiangiogenic therapy Most physicians are familiar with the paradigm long used in the development of cytotoxic anticancer drugs consisting of a three-step process in which phase I trials are conducted to test the safety of the agent and determine the dose. Investigators then look for surrogate markers of survival benefit, and most commonly, tumor shrinkage is used for this purpose. If antitumor activity is observed, phase II trials are conducted, usually involving single-arm trials of the

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new agent in patients with a specific tumor type. If the drug is found to be promising, its efficacy is compared with that of established treatments in large, randomized phase III trials. In the development of antiangiogenic agents, however, this three-step process may be entirely inappropriate, because, in the short term, tumor stabilization rather than tumor shrinkage may be the predominant effect. Therefore, when reviewing the results and designing early-phase trials of antiangiogenic agents, the objective responses may not be a very useful endpoint. Patient selection is also important. Traditionally, patients in early-phase trials frequently have advanced cancers that are refractory to treatment. Antiangiogenic agents, however, may be more effective at earlier stages of cancer progression and metastasis when microscopic islands of tumor cells can be forced to remain dormant before they develop vasculature and grow. Therefore, if patients with advanced and refractory cancers are used in the early testing of these drugs, potentially beneficial agents may be missed [154]. The duration of treatment also differs between cytotoxic and antiangiogenic drug trials. The main purpose of antiangiogenic therapy is to shift the balance between the negative and positive regulators of angiogenesis so that ‘‘hot spots’’ of angiogenesis are suppressed. Therefore, as long as the tumor cells exist and produce proangiogenic factors, antiangiogenic factors may need to be administered for months and perhaps years. Fortunately, the excellent safety profile of many of these drugs permits such an approach. Finally, cytotoxic and antiangiogenic therapies differ in terms of using toxicity to determine the optimal dose. Traditionally, toxicity is used as a surrogate for biologic activity, and the cytotoxic drug dose is adjusted, such that an unacceptable degree of toxicity is avoided but the maximum tolerated dose is given. In contrast, most antiangiogenic drugs have a broader therapeutic index. Further, if the toxic effects are caused by a mechanism distinct from that of the antitumor action, efficacy may be achieved without increasing doses to toxic levels. In addition, if all of the receptors of a growth factor are saturated by an antibody aiming to block that receptor, increasing the dose will be futile. Therefore, surrogate endpoints that correlate with antiangiogenic activity may need to be developed instead. Role of angiogenic factors in prognosis and risk stratification Angiogenic factors also are proving to be reliable biomarkers. For example, in B-cell chronic lymphocytic leukemia, serum vascular endothelial growth factor levels predict disease progression and refine the prognosis in patients with Binet stage A disease. The combination of vascular endothelial growth factor and b-2 microglobulin levels is a particularly powerful prognosticator. Specifically, in stage A patients, the median progression-free survival was only 13 months when the levels of both markers were higher than the median level and 40 months when the level of only one marker was elevated. Patients with no elevation in these markers did not even reach the median progression-free survival at 40 months [155].

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In non-Hodgkin’s lymphoma, high serum vascular endothelial growth factor and FGF-2 levels at diagnosis are associated with poor prognosis [156,157]. This was noted for all three grades of lymphoma and was still significant when tested with components of the International Prognostic Index. Patients who had the most elevated levels of vascular endothelial growth factor and FGF-2 had a nearly three times higher risk of death. There is evidence suggesting that vascular endothelial growth factor activation induces MCL1, a gene from the BCL2 family with antiapoptotic activity, and that the expression of vascular endothelial growth factor and MCL1 in non-Hodgkin’s lymphoma predicts a poor outcome [158]. In Hodgkin’s disease, high levels of vascular endothelial growth factor before and after treatment also correlate with shorter survival. This study failed to show an association between high pretreatment vascular endothelial growth factor and FGF-2 levels and survival in non-Hodgkin’s lymphoma; however, the sample size was much smaller than that of other similar studies and may have been too small to show an association [159]. In a study of patients with esophageal squamous cell carcinoma, vascular endothelial growth factor was found to be expressed in 44% of patients before treatment; this was associated with a poorer response to therapy and a lower 5-year survival rate [160]. In colorectal carcinoma, TGF-a, MMP-2, and insulin-like growth factor-II (IGF-2) appear to provide significant prognostic information that complements the pathological staging system. In one study, the expression of these markers in the tumors of patients with long disease-free survival and in those with metastatic disease was compared. When the levels of all three markers were elevated, the probability of developing liver metastasis was 99.5% [161]. In ovarian carcinoma, the expression of metastasis-related genes was examined as a prognostic factor. This revealed the ratio of type IV collagenase expression (mean of the expression of MMP-2 and MMP-9) to E-cadherin expression (MMP:E-cadherin ratio) to be a significant independent prognostic factor, even after adjustment for known prognostic factors, such as histology, stage, and age [162]. These are only a few examples of the establishing role of angiogenic factors in determining prognosis and predicting response to therapy in solid tumors and hematological malignancies. As more is learned about the underlying biology of tumor angiogenesis, angiogenic factors will become more instrumental in determining how individual cancers are managed. Role of antiangiogenic factors in treatment As noted previously, the purpose of antiangiogenic cancer therapy is to shift the balance between the negative and positive regulators of angiogenesis so that the angiogenic ‘‘hot spots’’ are suppressed, thereby preventing new blood vessel formation and causing the immature vasculature in tumors to regress (see Fig. 1). This is an achievable and attractive target, and the treatment has many advantages over conventional cytotoxic treatments (see Fig. 3). Selected antiangiogenic

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agents, their phases of development and their mechanisms of action are summarized in Table 4. Therapies directed against epidermal growth factor receptor Epidermal growth factor receptor is a tyrosine kinase receptor and has a dual role in cancer biology. With its ligands epidermal growth factor and TGF-a, it plays a role in the progression of epithelial cancers. It also controls in part the release of the proangiogenic factors, including vascular endothelial growth factor, FGF-2, and IL-8 [163 –165]. Studies in nude mice revealed that the treatment of pancreatic cancer xenografts with epidermal growth factor receptor tyrosine kinase inhibitors was associated with a significant reduction in the production of proangiogenic Table 4 Selected antiangiogenic agents Phase of development Target EGFR

Drug

Cetuximab (IMC-C225) ABX-EGF ZD1839 (Iressa) Erlotinib (Tarceva) CI-1033 VEGF Bevacizumab IMC-1C11 Semaxanib (SU5416) SU6668 PTK787/ZK 22584 ZD6474 Integrins Vitaxin EMD 121974 MMPs Marimastat Prinomastat Col-3 COX-2 Celecoxib Rofecoxib Ras BMS-214662 SCH-66336 R115777 Others Endostatin Angiostatin TNP-470 Thalidomide IM862 Neovastat

I

II

III

———————! ! ———————! ———————! ! ———————! ! ———————! ! ! ! ! ———! ———————! ———————! ———! ———————! ———————! ! ———! ! ———! ! ! ———————! ———————! ———————!

Mechanism Anti-EGFR Ab

EGFR-TKI Anti-VEGF Ab Anti-VEGFR-2 Ab VEGFR-1, -2 -3, c-kit TKI VEGFR-2, FGFR, PDGFR and c-kit TKI VEGFR TKI VEGFR-2 TKI antiintegrin avb3 antibody integrin avb3 antagonist MMPI MMPI MMPI COX-2 inhibitor COX-2 inhibitor FTI FTI FTI Multiple Multiple MetAP inhibitor Multiple Activate NK cells Multiple

Abbreviations: Ab, antibody; COX, cyclooxygenase; EGF, epithelial growth factor; EGFR, EGF receptor; FGFR, fibroblast growth factor receptor; FTI, farnesyltransferase inhibitor; MetAP, methionine aminopeptidase; MMPI, matrix metalloproteinase inhibitor; NK, natural killer; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

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molecules vascular endothelial growth factor and IL-8 by tumor cells. This, in turn, correlated with a significant decrease in microvessel density and an increase in apoptotic endothelial cells [166]. Because suppression of angiogenesis is an important component of the antitumor effects of epidermal growth factor receptor inhibitors, blocking both epidermal growth factor receptor and vascular endothelial growth factor receptor signal transduction made theoretical sense. Therefore, this approach was tested in nude mice with pancreatic cancer xenografts. Impressively, the pancreatic tumor volume was reduced by 97% when epidermal growth factor receptor and vascular endothelial growth factor receptor were blocked with tyrosine kinase inhibitors, and treatment included gemcitabine. Once again, the therapeutic efficacy directly correlated with a decrease in circulating levels of vascular endothelial growth factor and IL-8, a decrease in the microvessel density, and an increase in the apoptosis of endothelial and tumor cells [167]. Antitumor and antiangiogenic effects of therapies directed against epidermal growth factor receptor also were observed in nude mice with other tumor types such as bladder and prostate cancer [164,165]. The frequent overexpression of epidermal growth factor receptor in human tumors and the dual antitumor and antiangiogenic effects of antiepidermal growth factor receptor therapies provide an unparalleled opportunity to attack tumors at separate fronts with minimal side effects. Accordingly, antiepidermal growth factor receptor antibodies and epidermal growth factor receptor tyrosine kinase inhibitors are being evaluated in clinical trials. The initial results of the clinical trials have been particularly promising in patients with nonsmall cell lung cancer, head and neck, colon, pancreatic, and renal cell cancers [168 – 173]. Therapies directed against vascular endothelial growth factor and vascular endothelial growth factor receptor Vascular endothelial growth factor plays a paramount role in physiologic and tumor angiogenesis, as discussed previously. Specifically, vascular endothelial growth factor, which is secreted by the tumor cells, promotes endothelial cell mitosis, migration, and survival [24]. Endothelial cells, in return, produce growth and survival factors for tumor cells [5] and initiate the formation of new blood vessels, thus forming a paracrine feedback loop (see Fig. 2). The expression of vascular endothelial growth factor by tumor cells and its receptors by endothelial cells is increased in areas of active angiogenesis [174,175], and although vascular endothelial growth factor is essential for sustaining immature blood vessels, mature blood vessels no longer depend on vascular endothelial growth factor [38,176]. This selectivity, combined with its essential role in angiogenesis, makes the vascular endothelial growth factor paracrine system a very attractive potential target for antiangiogenic cancer therapies. Perhaps at least as important are the system’s antiapoptotic effects on endothelial cells [26], which make the combination of antivascular endothelial growth factor, cytotoxic, and radiation therapies a promising potential treatment strategy. Animal studies that block the action of vascular endothelial growth factor at the ligand or receptor level already have achieved promising results, including

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inhibition of new tumor or metastasis development and regression of existing tumors [177 –179]. Antivascular endothelial growth factor antibodies Bevacizumab. Bevacizumab (rhuMAb-VEGF), a recombinant humanized monoclonal antibody against vascular endothelial growth factor, has shown growth inhibitory effects on tumor cell cultures and xenografts [180] and can be administered safely with chemotherapy [181,182]. Toxicities include hypertension, proteinuria, and thrombosis. One particularly serious adverse effect, severe pulmonary hemorrhage, has been seen in 9% of the nonsmall cell lung cancer patients treated with bevacizumab in a phase II trial [183]. Squamous cell carcinoma histology and the presence of central cavitary tumors appeared to be associated with this serious side effect [184]. In early-phase trials, bevacizumab, alone or in combination with chemotherapy, showed promising activity against colorectal, renal cell, breast, and nonsmall cell lung cancers (Table 5). The addition of bevacizumab (10 mg/kg) to weekly irinotecan (CPT-11), 5-fluorouracil (5-FU), and leucovorin therapy in patients with advanced colorectal carcinoma has not resulted in any additional serious adverse effects [182]. Similarly, bevacizumab and 5-FU/leucovorin were tolerated well and appeared to improve the survival of patients with unfavorable prognostic indicators particularly [185]. On the basis of these findings, a phase III clinical trial has been started in patients with metastatic colorectal cancer, evaluating the addition of bevacizumab to standard treatment regimens [186]. Bevacizumab has shown promising antitumor activity in renal cell carcinoma. Indeed, a three-arm phase II trial comparing high-dose (10 mg/kg) and low-dose (3 mg/kg) bevacizumab therapy with placebo in metastatic renal cancer was Table 5 Results of the bevacizumab trials Trial phase

Disease characteristics

Treatment

Benefits

Notes

Colorectal [185,188]

II

Metastatic

FU/LV ± BV

May " RR and TTP

Renal cell [187]

II

Metastatic

Placebo vs. BV

" TTP

Breast [189]

II

Metastatic

BV

Occasional response

NSCLC [183,190]

II

Advanced

Carboplatin + paclitaxel ± BV

" RR and TTP

Preliminary; those with poor prognostic marker: best benefit Trial stopped early because of significant benefit; RR was low Preliminary; at 10 mg/kg, 6% CR (n=1); 18% (n=3) MR or PR Preliminary; nonsquamous histology also had "OS

Tumor

Abbreviations: BV, bevacizumab; FU, 5-fluorouracil; LV, leucovorin; OS, overall survival; MR, minor response; PR, partial response; RR, objective response rate; TTP, time to progression.

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stopped early when the interim analysis showed a highly significant prolongation of time-to-progression in patients treated with high-dose bevacizumab compared with placebo. There were only three partial remissions (2.7%), however, and all were in the high-dose group [187]. Single-agent bevacizumab, administered intravenously at a dose of 10 mg/kg every 2 weeks, has shown some antitumor activity against breast cancer [189], and a phase III trial comparing capecitabine with or without bevacizumab in patients with metastatic breast cancer has already finished accrual. Similarly, the combination of bevacizumab with carboplatin and paclitaxel in patients with previously untreated non-small cell lung cancer improved the response rate and time-to-progression compared with chemotherapy alone. In addition, the rate of life-threatening pulmonary hemorrhage was significantly less in patients with non-squamous histology than in those with squamous histology (3.8% versus 9%), and their median survival was also improved [183,191]. An advantage of bevacizumab may be that it still has antitumor activity when given as retreatment. For example, bevacizumab with or without chemotherapy was restarted in patients with advanced solid tumors whose disease progressed during the observation period after receiving bevacizumab for more than 1 year. Two of 16 patients subsequently achieved partial remission, and disease stabilized in 8 (range, 1.4 to 19.2 months) [192]. Currently, there are 18 active phase I and II trials evaluating bevacizumab in various solid tumors. Because of the importance of the vascular endothelial growth factor paracrine system in hematological malignancies, it also is being tested in poor-risk hematological malignancies [186]. IMC-1C11. This is a VEGR-2-specific chimeric monoclonal antibody. In mice, IMC-1C11 inhibited the proliferation of xenotransplanted human leukemias and significantly increased survival [193]. It is being evaluated in phase I trials for the treatment of colorectal cancer [194]. Preliminary results have shown it is tolerated well with no grade 3 or 4 side effects. In 36% of patients (n = 14), selflimited grade 1 bleeding episodes were observed that resolved without intervention. The development of antibodies could be a problem, as shown by the finding that antibodies developed in 70% of patients receiving lower doses. Interestingly, however, none of the patients receiving higher doses had this problem [195]. Vascular endothelial growth factor receptor tyrosine kinase inhibitors SU5416 and SU6668. SU5416 (semaxanib) and SU6668 are potent and selective tyrosine kinase inhibitors that target the receptors essential for angiogenesis, thereby preventing signal transduction after ligand binding. SU5416 targets VEGFR-1, -2, -3 signaling [196,197]. SU6668 blocks signal transduction from VEGFR-2, fibroblast growth factor receptor, and platelet-derived growth factor receptor [198]. These receptors are essential for endothelial cell mitosis, migration, and survival [24] and for the recruitment and proliferation of supporting cells [199,200]. The stem cell factor receptor c-kit, which is expressed in 60% to 80% of acute myelogenous leukemia (AML) blasts, is also inhibited by SU6668 and SU5416.

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This is important, because c-kit is essential for the development of normal hematopoietic cells and may have a functional role in AML, thereby providing a novel target for the treatment of AML [201]. In early-phase trials, the antitumor activity of SU5416 was particularly promising in renal cell carcinoma, mesothelioma, and colorectal cancer. Unfortunately, phase III trials testing SU5416 with standard chemotherapy in advanced colorectal cancer were closed after an interim analysis reportedly showed a lack of clinical benefit [202]. Following this, Sugen, the producer of SU5416, announced that the company will stop developing the drug after ongoing trials are finished. SU6668 is at earlier phases of development. Preliminary results from phase I trials in solid tumors revealed that SU6668 is tolerated well, with no serious toxicities and only mild-to-moderate nausea, diarrhea, fatigue, and dyspnea. Even when the daily dose was escalated from 100 mg/m2 to 2400 mg/m2, a maximum tolerated dose was not reached. Disease was stabilized in a few patients with nonsmall cell lung cancer, desmoid tumor, or sarcoma who had participated in the study for more than 1 year [203]. On the basis of results from pharmacokinetic studies [204] and animal data revealing an early decrease in tumor perfusion followed by an increase before the next dose [205], twice-daily dosing was tested. SU6668 was tolerated well with no serious adverse effects up to a dose of 300 mg/m2 twice daily, and the most common mild adverse effects consisted of urine or stool discoloration, gastrointestinal effects, fatigue, muscle aches, and joint, chest or back pain. Dose-limiting toxicities encountered at doses of 400mg/m2 and 800mg/m2 twice daily included pericarditis, pleuritic chest pain, and grade 3 thrombocytopenia [206]. PTK787/ZK 22584. PTK787/ZK 22584 (ZK) is a potent and selective vascular endothelial growth factor receptor-tyrosine kinase inhibitor. At higher concentrations, it also inhibits platelet-derived growth factor receptor and the stem cell factor receptor, c-kit. It has excellent oral bioavailability. ZK caused tumor regression and suppressed metastases and angiogenesis with no adverse effects on wound healing in animal studies [207,208]. Moreover, in mice, ZK rendered radiation-resistant tumors responsive to radiation as the other vascular endothelial growth factor receptor tyrosine kinase inhibitors do [209]. In two phase I trials, ZK was tested in patients with colon cancer and glioblastoma multiforme. It was mostly tolerated well with primarily mild adverse effects that included nausea, fatigue, and dizziness [210]. Grade 3 toxicities included deep vein thrombosis and elevated liver enzyme levels [211]. The drug had some activity against both colon cancer and glioblastoma multiforme. More than half of patients with heavily treated colon cancer metastatic to the liver had stable disease while on treatment. ZK is in phase I trials in patients with AIDS-associated Kaposi’s sarcoma, colon cancer, glioblastoma multiforme, and, von Hippel-Lindau syndrome. ZD6474. ZD6474 is an orally administered potent tyrosine kinase inhibitor that blocks the signal transduction of VEGFR-2. It also shows some activity against epidermal growth factor receptor tyrosine kinase [212]. In animal studies, ZD6474 inhibited the growth of human lung and prostate cancer xenografts and

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induced regression even in larger tumors [213]. In an ongoing phase I trial, the drug was tolerated very well with minimal adverse effects. At higher doses, grade 3 diarrhea and skin rash were observed in several patients. This was most likely because of the ability of ZD647 to inhibit epidermal growth factor receptortyrosine kinase [214,215]. AG013736. AG is a tyrosine kinase inhibitor that selectively blocks signal transduction from VEGFR-1 and-2 and PDGFR-b. The drug also blocks the c-kit receptor expressed by neuroendocrine tumors and small cell lung cancer, and by a significant percentage of AML blasts. The oral, twice-daily administration of AG significantly inhibited tumor growth in several human xenograft and murine tumor models. In particular, it significantly inhibited human melanoma metastasis to the lungs and the lymph nodes in mice. There is evidence that the underlying mechanism of the antitumor effects of AG is antiangiogenesis. AG is in the early stages of development, and phase I trials in patients with solid tumors were initiated recently [216]. Integrin avb3 antagonists Vitaxin is a humanized anti-integrin avb3 antibody in the early phases of clinical trials. It is administered intravenously weekly or every 3 weeks and is associated with mild adverse effects that include the commonly seen antibody infusion reactions, fever, chills, nausea, and flushing. Oral premedication with acetaminophen and diphenhydramine before each Vitaxin infusion appeared to prevent fever, and the antibody infusion reactions decreased in incidence after the first infusion [217 –219]. In clinical trials, rare responses and occasional disease stabilization were seen in patients receiving vitaxin. In a phase I study, the tumor volume was reduced significantly in one patient with leiomyosarcoma [217]. A subsequent phase I study of Vitaxin in patients with advanced leiomyosarcomas failed to show any tumor regression, but 5 of 15 patients had stable disease [219]. EMD 121974, a cyclic RGD (Arg-Gly-Asp) pentapeptide, is an avb3 and avb5 integrin antagonist that has proven active against brain tumors and melanoma in preclinical studies [220] and is being tested in phase I/II trials [186,221]. According to preliminary results, adverse effects were mostly mild and included fatigue, rash with pruritus, and nausea [222]. Cyclooxygenase inhibitors Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins by blocking the cyclooxygenase activity of the enzyme prostaglandin G/H-synthase. Of the two isoforms of cyclooxygenase, COX-1 is expressed constitutively in many tissues. COX-2 expression, while normally limited to brain and kidneys, is induced widely in various tumors [223 – 227], including head and neck, colon, lung, breast, prostate, esophagus, and urinary bladder tumors [228]. Epidemiological studies have shown a significant reduction in the risk of developing colon, breast, and lung cancer in people treated with aspirin

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[229,230]. Moreover, in patients with familial adenomatous polyposis, two randomized studies have found that sulindac [231] and the selective COX-2 inhibitor celecoxib [232] suppress growth and cause the regression of existing polyps. Animal studies also have shown that these drugs can inhibit the growth of tumors of the esophagus, stomach, skin, lung, breast, prostate, and urinary bladder [228]. It appears that the preventive and therapeutic effects of COX-2 inhibitors on tumors are caused by the restoration of apoptosis and the inhibition of angiogenesis [31,233,234]. COX-2 inhibitors and indomethacin suppress hypoxia-induced vascular endothelial growth factor/VEGFR-1 expression and angiogenesis (see Fig. 5). This is mediated by increased von Hippel-Lindau expression, leading to the degradation of HIF-1a. HIF-1a, on the other hand, is essential for the increased transcription of vascular endothelial growth factor in response to hypoxia. A selective COX-2 inhibitor may abolish the hypoxia-induced accumulation of HIF-1a [31] completely. In addition, COX-2 inhibitors interfere with avb3 integrin-mediated endothelial cell migration and angiogenesis [235]. On the basis of these data, the COX-2 inhibitors celecoxib and rofecoxib are being tested in phase I-III trials for the treatment and prevention of cancer [186]. Preliminary results of early-phase trials of celecoxib suggest that it may have a place in the treatment of colorectal and non-small cell lung cancer in combination with cytotoxic and/or radiation therapy. In colorectal cancer, a retrospective study in patients with previously treated metastatic colorectal cancer revealed that the addition of daily oral celecoxib to capecitabine may significantly prolong time-to-progression. Celecoxib-treated patients also were less likely to experience hand-foot syndrome and severe diarrhea compared with patients treated with capecitabine alone [236]. Other studies also suggested that there was a decrease in the severity of diarrhea [237] and neutropenia [237,238] when celecoxib was added to chemotherapy for colorectal cancer. In patients with non-small cell lung cancer, major clinical and pathological response (greater than 95% tumor necrosis) rates were higher than historical response rates (75% versus 56% and 37% versus 6%, respectively) in those receiving celecoxib preoperatively along with carboplatin and paclitaxel chemotherapy [239]. Celecoxib generally is tolerated well with no additional adverse effects. Vascular events such as deep vein thrombosis, myocardial infarction, and stroke were observed in some studies in up to 13% of patients, however [238]. Previous studies of COX-2 inhibitors in the treatment of rheumatoid arthritis suggested that they increase the risk of cardiovascular events but that low-dose aspirin may reduce this risk [218]. Accordingly, prophylaxis with low-dose aspirin should be considered in all high-risk cancer patients. Endostatin Endostatin raised a great deal of interest in preclinical studies when it induced slowing and significant regression of tumors by inhibiting angiogenesis [22,

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240 – 243]. Moreover, there was no evidence of toxicity. Phase I trials of intravenous recombinant human endostatin (rhEndostatin), however, while demonstrating the same excellent safety profile, unfortunately have shown limited antitumor activity [244,245]. Interestingly, tumor biopsy specimens obtained prior to and 8 weeks after the initiation of treatment in a phase I trial of endostatin did not show some effect on tumor and endothelial cell apertures [246]. Continuous intravenous infusion of endostatin may be preferable because of the large variations between the peak and nadir serum concentrations when the drug is given as bolus [245], and because techniques providing sustained endostatin delivery achieved impressive results in preclinical studies [22,241,247]. Results of a phase I trial utilizing both intravenous bolus and continuous infusion of endostatin in refractory solid tumors have been reported recently. No toxicity was observed except for a grade 1 rash in 3 of 28 patients. No effect on the estimated blood flow was seen in contrast-enhanced MRI scans. Two patients (both with pancreatic neuroendocrine tumors) experienced a minor response, however, and 4 patients had prolonged (longer than 6 months) stable disease. [248] Phase I/II trials are underway to evaluate endostatin in different schedules and in combination with chemotherapy. Angiostatin Early data from the first phase I trial of intravenous recombinant human angiostatin (rhA) revealed no dose-limiting toxicity. Skin rash developed in about 25% of the patients but did not progress during therapy. Patients with surgical wounds also did not experience any problems. Of note, the antibody titer against rhA was positive in 3 of 15 patients [249]. Twice-daily subcutaneous injection of angiostatin also was tolerated well in patients with advanced cancer, even after prolonged use. Plasma concentrations of angiostatin were within the range of those of preclinical studies showing biological activity. Prolonged disease stabilization was observed in 7 of 24 patients [250]. Other antiangiogenic agents TNP-470. TNP-470 (also known as AGM-1470) is the synthetic form of the natural antiangiogenic compound fumagillin, which inhibits endothelial cell migration, proliferation, and capillary tube formation. Recent data suggest that the activity of TNP-470 is mediated through inhibition of methionine aminopeptidase-2 (MetAP2), cyclin-dependent kinase 2 (CDK2), and retinoblastoma (Rb) protein phosphorylation. Methionine aminopeptidases remove the N-terminal methionine from peptides, and MetAP2 regulates protein synthesis by protecting the subunit of eukaryotic initiation factor-2 from phosphorylation. Nondividing cells do not show immunodetectable levels of this enzyme, and its inhibition results in apoptosis in mesothelioma cells. Moreover, MetAP2 positively regulates Bcl-2 expression. This, on one hand, contributes to the up-regulation of

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telomerase activity in the nucleus and, on the other, inhibits caspase activation [251,252]. In addition, TNP-470 causes the accumulation of the CDK inhibitor p21CIP/WAF. CDKs drive cell-cycle progression, and their inhibition by p21CIP/WAF inhibits Rb protein phosphorylation and cell-cycle arrest at the G1 to S transition. Growth arrest in response to TNP-470 by way of this mechanism was not observed in other primary cell types such as fibroblasts [253]. In animal studies utilizing human tumor xenografts, TNP-470 significantly reduced tumor size and the occurrence of metastases in a variety of cancers, including slowly growing and poorly vascularized tumors [254 – 258]. Observations that may be important for future clinical studies were that the TNP-470 treatment was most effective when initiated while the tumors were still microscopic in size, and larger tumors responded to higher doses [259,260]. Animal studies also showed that TNP-470 prevents healing of fractures [261] and induces a significant delay in murine cutaneous wound healing [262]. Therefore, close attention for these effects is called for designing human trials. The principal dose-limiting toxicity of TNP-470 is a characteristic neuropsychiatric symptom complex consisting of ataxia, decreased concentration and short-term memory, insomnia, and agitation that resolves completely several weeks after the cessation of therapy [263,264]. Other adverse effects include fatigue and nausea, but most patients tolerate the drug well. In phase I studies utilizing single-agent alternate-day or weekly intravenous dosing, there were rare and often minor objective responses in patients with AIDS-associated Kaposi’s sarcoma, and cervical and renal cell carcinomas [265 – 267]. Disease stabilization was also observed in some patients. One patient with colon cancer that had metastasized to the lung received TNP-470 after the resection of all measurable disease and was disease-free for 17 months [264]. Although this could be the natural behavior of colon cancer, it is consistent with animal studies showing TNP-470 to be particularly effective against microscopic disease [260]. Thalidomide. This drug has been shown to inhibit angiogenesis induced by FGF-2 or vascular endothelial growth factor. In humans, it is converted to metabolites that have antiangiogenic activity. Thalidomide is being evaluated in the treatment of various solid tumors, multiple myeloma, and other hematological malignancies. Results have been disappointing in solid tumors but particularly promising in multiple myeloma. Thalidomide’s antiangiogenic effects are believed to be only part of its antimyeloma activity, however. It also may modulate adhesion molecules, inhibit TNF-a, down-regulate lymphocyte surface molecules, lower CD4:CD8 peripheral lymphocyte ratios, and have direct effects on myeloma cells themselves. Sedation and constipation are the most common adverse effects in cancer patients. The most serious adverse effect associated with thalidomide use is peripheral neuropathy, which occurs in approximately 10% to 30% of patients. This typically abates upon prompt discontinuation of the drug, but longstanding sensory loss has been documented. The risk of developing peripheral

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neuropathy during thalidomide treatment increases when high cumulative doses are administered and is especially high in the elderly. It should be used with caution when there is a prior history of neuropathy and when it is used in combination with other agents known to have neurotoxic effects. There also may be an increased incidence of thromboembolic events, particularly when the drug is combined with steroids or with anthracycline-based chemotherapy. Possible cardiovascular effects of thalidomide include bradycardia and hypotension. The risk of adverse cardiovascular events appears greater in older patients with coronary artery disease taking multiple blood pressure-lowering medications [268]. IM862. This is a naturally occurring and intranasally administered small peptide that is believed to inhibit angiogenesis and tumor growth by activating natural killer cells and inhibiting vascular endothelial growth factor production. In early trials, IM862 showed activity against ovarian cancer and AIDSassociated Kaposi’s sarcoma, and was tolerated very well with no serious adverse effects [269]. IM862 raised hopes in a phase II study of AIDS-associated Kaposi’s sarcoma when major responses were seen in 36% of patients. Moreover, stable disease lasting more than 6 months was observed in 48% of patients and some of the complete remissions were durable [270]. Unfortunately, the preliminary analysis of the phase III trial of IM862 in AIDS-associated Kaposi’s sarcoma failed to show any clinical benefit [271], which also brought other IM862 trials to a halt. Neovastat. Neovastat (Æ-941) is an extract derived from shark cartilage that exhibits antitumor and antimetastatic activity in human tumor xenografts. In animal studies, it was observed to inhibit metastasis in a dose-dependent manner [272]. Neovastat appears to target multiple steps of tumor angiogenesis. First, the tissue inhibitors of matrix metalloproteinase-like proteins in the extract inhibit matrix metalloproteinases [273]. Second, it may interfere with FGF-2mediated angiogenesis [272]. Third, it blocks vascular endothelial growth factor-dependent vascular sprouting by competing for the binding of vascular endothelial growth factor to VEGFR-2 [70], and fourth, it may induce the expression of angiostatin [274]. In a phase II trial in patients with solid tumors, neovastat was tested at two different doses, 60 mL per day and 240 mL per day, and showed dose-dependent activity in refractory renal cell cancer [275]. The median survival of patients who received the higher dose was more than twice that seen in patients receiving the lower dose (16.3 months versus 7.1 months). In addition, at 2 years, no patients in the low-dose group were alive, compared with 36% of those in the high-dose group. A subgroup analysis of a large phase II trial revealed a statistically significant prolongation of survival in lung cancer patients, too (6.15 months versus 4.63 months) [276]. The drug is being evaluated in phase III trials in patients with lung and renal cancers. In nude mice, neovastat significantly decreased the development of bone metastasis by implanted human breast cancer cell lines, suggesting that the drug also could prevent bone metastasis in cancer patients [277].

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PS-341. Tumor cells are heavily dependent on proteasome-regulated proteins for their growth and interaction with stromal cells. For example, NF-kB, a transcription factor, appears to be an important driver of myeloma cell growth in the marrow, up-regulating the expression of IL-6, vascular endothelial growth factor, cell-adhesion molecules, and antiapoptotic factors. NF-kB activation is blocked by PS-341, a selective inhibitor of the proteasome. PS-341 was generally tolerated well in phase I trials, with clinical activity apparent in patients with multiple myeloma. On the basis of these observations, a phase II trial is in progress in patients with this disease [278]. Antiangiogenic vaccines and immunotherapy The tumor endothelium could represent a novel target for active and passive immunotherapies of cancer. This is because endothelial cells are genetically stable, potentially avoiding the development of resistance. As a proof of this concept, Scappatici et al [279] vaccinated mice with endothelial cells. Tumors did not develop in half of the mice that received the syngeneic vaccine after B16F10 melanoma challenge, and microvessel density was lower in those in which tumors did develop. An epidermal growth factor-based vaccine has been tested in two phase I studies of patients with non-small cell lung cancer (n = 40). Pooled data from these studies have shown that median survival was significantly better in patients with higher antiepidermal growth factor antibody titers than in the patients with lower antibody titers (9.1 months versus 4.5 months) after immunization with epidermal growth factor [280]. Vascular mapping There is emerging evidence suggesting that an individualized library of peptides homing to only certain tissue-specific vascular beds may be built, thus creating a vascular map for each person and disease. Such an individualized vascular map could then be utilized to deliver therapeutic agents only to the desired locations. This strategy already has been applied to animal models and allowed tissue-specific targeting of normal blood vessels [281] or tumor-specific angiogenesis [282,283]. Recently, Arap et al [284] reported a successful ligandreceptor map of human blood vessels. They injected a phage-display peptide library into a terminally ill patient and then obtained tissue samples to determine the distribution of the peptides. In the near future, it may be routinely possible to obtain disease- and tissue-specific molecular maps of blood vessels, and this information could be exploited for targeted therapy. Antiangiogenic agents and radiotherapy Oxygen is the most important modifier of the biological effect of ionizing radiation. If antiangiogenic agents decrease the blood flow to a tumor, would this therefore lessen the therapeutic effects of radiation? In fact, animal studies have shown just the opposite. Antiangiogenic agents actually can increase the response

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to radiation therapy [285 –289]. This is because, even though the antiangiogenic agents can decrease the blood flow to a tumor when administered for weeks to months, initially, blood flow and oxygenation are increased [244,290]. After treatment with certain antiangiogenic agents, extravasation decreases, and as a result, tumor interstitial pressure is lowered, permitting better blood flow and oxygenation. The response to radiation therapy still is augmented under hypoxic conditions, however, suggesting that endothelial cell radiosensitization or loss of the antiapoptotic and mitogenic factors secreted by endothelial cells may be at least as important as oxygenation [291]. Patients are currently being accrued to clinical trials testing combinations of radiotherapy, chemotherapy, and antiangiogenic therapy. Chemotherapy and antiangiogenesis Chemotherapeutic agents generally have a cytotoxic effect on rapidly proliferating cells. Therefore, if endothelial cells are proliferating actively during angiogenesis, should we not expect chemotherapy to have antiangiogenic properties? In fact, it appears that endothelial cells, just like hematopoietic cells, recover during the long intervals between treatments. Thus, it is possible to use an ‘‘antiangiogenic schedule’’ (also called ‘‘metronomic dosing’’) of chemotherapy to minimize this recovery. In this schedule, cytotoxic agents are given at lower doses but without interruption, thereby achieving the endothelial cell apoptosis followed by secondary tumor cell apoptosis. In animal studies, antiangiogenic scheduling was able to eradicate tumors, particularly when combined with angiogenic inhibitors. More importantly, this was achieved with reduced toxicity to the host and even in the presence of resistance to the same agents given at conventional doses [292,293]. For example, after continuous treatment with ‘‘antiangiogenic’’ low-dose vinblastine with the VEGFR-2 specific monoclonal antibody DC101, large tumors that developed from neuroblastoma cell line xenografts in mice underwent full and sustained regressions that lasted for longer than 6 months [293]. Indeed, the success of certain chemotherapy schedules already used in clinical practice might be because of antiangiogenic activity. For example, significant proportions of breast and ovarian cancer patients (as high as 62.5%) respond to taxanes when given weekly at lower doses, even after they have acquired resistance to the maximum tolerated dose given once every 3 weeks. [294,295]. A clinical application of antiangiogenic chemotherapy in metastatic breast cancer was reported recently by Colleoni et al [296] and involved low-dose, oral, daily methotrexate and weekly cyclophosphamide dosing. The overall rate of clinical benefit (complete response plus partial response, plus stable disease longer than 24 weeks) was 31.7%, which was very encouraging, considering that most of these patients had progressive disease with visceral metastases at study entry. Remarkably, this was achieved in the absence of any serious toxicity.

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On the basis of these findings, combinations of antiangiogenic factors with metronomic dosing of chemotherapy appear to represent a compelling and lowtoxicity cancer treatment strategy for new clinical trials. Resistance to antiangiogenic therapy Tumors are less likely to develop resistance to antiangiogenic therapy, because the endothelial cells are genetically stable as opposed to their malignant counterparts, tumor cells [7]. The susceptibility of tumor cells to hypoxia may vary, however, leading to decreased response to antiangiogenic agents. Mutation of the p53 tumor suppressor gene could be one such modifier of the response to antiangiogenic therapy. This is because p53-deficient cells may display a diminished rate of apoptosis under hypoxic conditions. Indeed, tumors in p53-deficient mice are less responsive to antiangiogenic therapy [297]. Role of antiangiogenic agents in cancer prevention The angiogenic ‘‘switch’’ is turned on very early during tumorigenesis and may be an important step in the progression of in situ to invasive carcinoma. It is proposed that inhibiting angiogenesis at this early step may provide primary prevention of cancer. A series of substances that are proposed as possible cancer chemopreventive agents, such as the catechins from green tea [273] and flavonoids from soybeans, retinoids, and NSAIDs, have shown antiangiogenic properties when tested in vitro and in vivo [298]. For example, NSAIDs reduce the risk of colon cancer in familial polyposis [231], likely by inhibiting angiogenesis [31,235]. A study of carcinogen-induced breast cancer in rats revealed that endostatin prevented the onset of multiple primary tumors and significantly slowed the growth of existing tumors [299]. In addition, the administration of endostatin for longer than 1 year in human trials revealed an excellent safety profile. The concept of ‘‘angioprevention’’ therefore may be developed into another interesting application of antiangiogenic agents, but there is much more to be learned about such factors, as the long-term effects of antiangiogenic agents on wound healing and reproductive functions before angioprevention could be included in the armamentarium against cancer.

Summary Antiangiogenic drugs are unique for having highly specific targets while carrying the potential to be effective against a wide variety of tumors. Moreover, some of the major limitations of cytotoxic therapies likely will be avoided by this entirely new class of anticancer weapons. After the realization of the potential advantages of antiangiogenic therapy, the field of angiogenesis research is growing exponentially. Still, there is much to learn about the machinery that tumors use to recruit new blood vessels, and the

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results of the clinical trials will show the best way to apply that knowledge for cancer therapy.

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