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1、.Anti-angiogenictreatmentstrategiesfor the therapyof endometriosisM.W.Laschke*and M.D. MengerInstitute for Clinical& Experimental Surgery,University of Saarland,D-66421 Homburg/Saar, GermanyCorrespondence address.Tel: + 49-6841-162-6554; Fax: + 49-6841-162-6553; E-mail:matthias.laschkeuks.euSubmitte
2、don February14, 2012; resubmitted on May 2, 2012; accepted on May 17, 2012tableofcontents?Introduction?Methods?ResultsGrowth factor inhibitorsEndogenousangiogenesisinhibitorsFumagillinanaloguesStatinsCyclo-oxygenase(COX)-2 inhibitorsPhytochemicalcompoundsImmunomodulatorsDopamine agonistsPeroxisomepr
3、oliferator-activated receptor (PPAR) agonistsProgestins,danazoland gonadotropin-releasinghormone (GnRH) agonistsOther agents?Potential impact of anti-angiogenictreatment in future endometriosis therapy?Conclusionsbackground:Angiogenesis,i.e. the development of new blood vesselsfrom pre-existingones,
4、 representsanintegralpart in the patho-genesisof endometriosis. During the lastdecade, anincreasingnumber of studieshavetherefore focusedon the anti-angiogenictreatment ofthe disease.The present review provides a systematic overview of these studies and critically discussesthe future role of anti-an
5、giogenictherapy in the multimodal managementof endometriosis.methods:Literature searcheswere performed in PubMed, MEDLINE andISIWeb of Knowledge for original articlespublishedbefore theend of March 2012, written in the Englishlanguageand focusingon anti-angiogenic approaches for the therapy of endom
6、etriosis. Thesearchesincluded both animal and human studies.results:Numerous compounds of different substancegroupshavebeen shown to exert anti-angiogeniceffectson endometriotic lesionsunder experimental in vitro and in vivo conditions. These include growth factor inhibitors, endogenous angiogenesis
7、inhibitors, fumagillinanalogues,statins, cyclo-oxygenase-2inhibitors, phytochemical compounds, immunomodulators, dopamine agonists,peroxisome prolifer-ator-activated receptor agonists, progestins, danazol and gonadotropin-releasing hormone (GnRH) agonists.However, clinical evidencefor their ef?cacyi
8、n anti-angiogenicendometriosis therapy is still lacking.conclusions:Anti-angiogeniccompounds hold greatpromise for the future treatment of endometriosis becausethey mayinhibit theestablishment of new endometriotic lesionsin early stagesof the diseaseor after surgicaltreatment. Further experimental s
9、tudies,controlledclinical trials in particular, are required now to clarify which compounds ful?l these expectations without inducing severe side effects inpatients with endometriosis.Keywords:endometriosis / angiogenesis/ vascularization/ anti-angiogenictherapy / vascularendothelial growth factor&T
10、he Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.For Permissions,please email: HumanReproductionUpdate,Vol.18,No.6pp. 682702, 2012Advanced Access publication on June 19, 2012doi:10.1093/humupd/dms026 by g
11、uest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from IntroductionEndometriosis is a benign gynaecologicaldisease,which is character-ized by the presence of endometriotic lesionsconsistingof functionalendometrial glands and stroma outside the uterine cavity (Galle,1989). The prev
12、alence rate of the condition is high among womenof reproductive age,causingsigni?cantannual costs in the healthcaresystem (Simoens et al., 2007). Although some affected women mayremain asymptomatic, endometriosis is typically associated with awide spectrum of pain symptoms (Stratton andBerkley, 2011
13、) and in-fertility (Garrido et al., 2002;Bulletti et al., 2010). Thisoften leadsto aseverely limited quality of the patientsprivate and professional life(Gilmour et al., 2008).Current approaches for the treatment of endometriosis involvepharmacological therapy andsurgical removalof endometrioticlesi
14、ons. Because the proliferation and long-term survival of ectopicendometrial tissue is estrogen-dependent (Giudice and Kao, 2004),classicalpharmacologicaltherapies are primarily aimed at the suppres-sion of endogenous estrogen production by the application of oralcontraceptives, GnRH agonists,androge
15、nic agents or aromataseinhi-bitors (Nothnick, 2010). However, this type of medication is asso-ciated with substantial side effects, which limits prolonged exposure,and endometriosis is likely to recur following treatment cessation(Fedele et al., 1994; van Langendonckt et al., 2008; Pullen et al.,201
16、1). Surgicalremoval of endometriotic lesionsis not only temporar-ily effective, but also associated with a high recurrence rate (Fedeleet al., 1994; Guo, 2009). In addition, dependent on the localizationof the lesion and the severity of the disease,surgicalremoval can betechnically challengingand be
17、ars the risk of urological or colorectalcomplications. Thus, there is an urgent need for the development ofnovel treatment strategies for endometriosis, which guarantee thelong-term cure of affected patients. For this purpose, key processesin the pathogenesis of endometriosis have been identi?ed, wh
18、ichmay serve as potential therapeutic targets.One of thesekey processesis angiogenesis,i.e. the development ofnew blood vesselsfrom the pre-existing ones (Carmeliet and Jain,2011). In fact, similar to tumours and their metastases, survival ofendometriotic lesions is crucially dependent on the establ
19、ishment ofan adequate blood supply (Groothuiset al., 2005; Becker andDAmato,2007; May andBecker, 2008; Taylor et al., 2009). Accord-ingly,early developinglesions,which are the most active ones, haveatypically pink-red appearance because of their high vascular density(McLaren, 2000; Laschkeet al., 20
20、11a; Fig.1) and exhibit anincreasednumber of immature pericyte-free microvesselswhen compared withthe black lesionsof later stages(Nisolle et al., 1993; Matsuzakiet al.,2001). Moreover, the peritoneal ?uid from patients with endometri-osis contains highamounts of various angiogenicgrowth factors and
21、reduced concentrations of anti-angiogenic compounds (LaschkeandMenger, 2007). Finally,the eutopic endometrium from patients withendometriosis has been shown to exhibit an increasedangiogenicpo-tential when compared with healthy women (Chung et al., 2002; Huret al., 2006). This may contribute to the
22、initiation of the diseasebyretrograde menstruation of highly angiogenicendometrial fragmentsinto the peritoneal cavity. Based on these ?ndings, endometriosishas been classi?ed as a typical angiogenic disease,such as cancer,psoriasis or diabetic retinopathy (Healy et al., 1998).Since JudahFolkmansrev
23、olutionaryidea of ?ghting cancer byattacking its blood supply (Folkman, 1996, 1971), anti-angiogenictherapy hasbeen proposed asa promising strategy for severalangio-genicdiseases,including endometriosis. During the last decade, anin-creasing number of studies have focused onthe treatmentofendometrio
24、tic lesionsby application of different anti-angiogeniccom-pounds. In the present review, we provide a systematic overview ofthese studies and highlight themostinteresting anti-angiogenicFigure1Typical macroscopic appearance of a developing endo-metrioticlesion, which was surgically induced under exp
25、erimentalconditions by suturing a mouse uterine tissue sample to the periton-eal wall of a recipient animal, according to Laschke et al. (2011a).Note the red colour of the lesion, which is causedby its high micro-vasculardensity and haemorrhages occurring during the early vascu-larization process. S
26、calebar: 1.6 mm.TableI Inclusionand exclusioncriteriafor studiesofanti-angiogenictreatmentstrategiesin endometriosisin the presentreview,as listedin TableII.InclusioncriteriaExclusioncriteriaOriginal articlesEditorials, letters to the editor,abstracts, duplicate papers, reviews,case reportsEnglishla
27、nguageLanguageother than EnglishAll electronically listed publicationsin PubMed, MEDLINE and ISIWebof Knowledge until end of March2012Publications listed after March 2012Studies focusing on anti-angiogeniceffects of compounds onendometriosisStudies focusing on basicmechanisms of angiogenesisin theeu
28、topic endometriumAnimal and human studies, in vitroand in vivoStudies analysingangiogenesisinendometriosis independent fromapplication of anti-angiogeniccompoundsAnti-angiogenic therapy of endometriosis683 by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from approaches.Moreo
29、ver, we critically discussthe potential future role ofanti-angiogenictherapyinthemultimodalmanagementofendometriosis.MethodsLiterature searcheswere performed in PubMed, MEDLINE and ISIWeb ofKnowledge for original articles writtenin the English languageand elec-tronically listed until end of March 20
30、12, which focused on anti-angiogenictreatmentstrategies for the therapy ofendometriosis.The searchesincluded the key words endometriosis,endometriotic,endometrium ,endometrialand ectopicendometrium , which were paired with thekey wordsangiogenesis,vascularizationand anti-angiogenic.Thesearchesinclud
31、ed both animal and human studies. Inclusion and exclusioncriteria for the studies selected are shown in Table I.ResultsWe detected 49 original articles ful?llingthe inclusion criteria of ourliterature search(Fig.2, Table II). Almost all of these articles reportedexperimental studies,which were perfo
32、rmed in different in vitroand invivo endometriosis models. The application and suitability of thesemodels for the analysisof angiogenesisin endometriosis haspreviouslybeen reviewed in detail (Laschkeand Menger, 2007). In general, wefound that the studies comprised many anti-angiogenic compounds,whic
33、h were not restricted to one speci?csubstancegroup. The anti-angiogenicproperties of most of these compounds had alreadybeendemonstrated in tumour studies before they were analysed in thecontext of endometriosis. Table III provides anoverview of their spe-ci?c targets or mechanisms of action and a s
34、election of relevant sideeffects reported in experimental and clinical studies.GrowthfactorinhibitorsDuring the last years, several angiogenic growth factors have beenidenti?ed, which are expressedin endometriotic lesionsand releasedinto the peritoneal ?uid of patients with endometriosis (Taylor et
35、al.,2002). The most prominent and the most studied one is vascularendothelial growth factor (VEGF), which acts as a potent selectiveendothelial mitogen and survival factor (Leung et al., 1989; Lazarusand Keshet, 2011). Ofinterest, highly active red endometrioticlesions contain the highest VEGF conce
36、ntrations when comparedwith other lesion types (Donnez et al., 1998). In addition, peritoneal?uid concentrations of VEGFcorrelate signi?cantlywith the stageofendometriosis (Shifren et al., 1996).VEGFis a dimeric glycoprotein, whose biologicaleffects are primar-ily mediated by two high-af?nity recept
37、or tyrosine kinases on thesurface of microvascular endothelial cells, i.e. VEGFR-1 (Flt-1) andVEGFR-2(Flk-1/KDR)(de Vries et al., 1992; Millauer et al., 1993).Hull et al. (2003)were the ?rst to reportthat treatment withbotha soluble truncatedFlt-1-receptorand an af?nity-puri?edVEGF-antibodysigni?can
38、tlyinhibits the growth of developingendome-triotic lesionsin nude mice by disrupting their immature microvascu-lature. Similar results were found by Nap et al. (2004; 2005) whotreated endometrioticlesions with an anti-VEGF antibody in thenude mouse modeland the chicken chorioallantoicmembrane(CAM) a
39、ssay. These ?ndingsindicate that blockade of VEGFsignallingprevents the establishmentof endometriotic lesions.In the future, thismay be achieved by VEGF-targetedgene therapy (Rein et al., 2010).However, VEGFtargeting is currently much easier to realize in clinicalpractice by the application of an an
40、ti-VEGFantibody, suchas bevaci-zumab (Avastin). Bevacizumabis a recombinant anti-VEGFmonoclo-nal antibody, which is already approved by the US Food and DrugAdministration (FDA) as a ?rst-line treatment for patients sufferingfrom metastatic colorectal cancer in combination with chemotherapy(Ferrara e
41、t al., 2005). Recently,Ricci et al. (2011) demonstrated thattreatment with this antibody signi?cantlydiminishes vascular densityand cell proliferation and increasesapoptotic cell death in surgicallyinduced endometriotic lesionsof BALB/c mice. Moreover, bevacizu-mab reduces VEGFlevelsin the peritonea
42、l ?uid of the animals.None-theless,despite thesepromising experimental ?ndingsit isunlikely thatbevacizumab willeverbeapproved forendometriosis therapy,because this may be accompanied by severe side effects, such ashypertension, proteinuria, impaired wound healing, gastrointestinalperforation, throm
43、bosis and bleeding (Kamba and McDonald, 2007).The most potent stimulusfor the up-regulation of VEGFis hypoxia(Shweikiet al., 1992), which prevents the intracellular degradation ofubiquitously expressed hypoxia-inducible factor-1a (HIF-1a; Harris,2002). Under hypoxic conditions, this factor transloca
44、tes into thenucleus, heterodimerizes with HIF-1b /aryl hydrocarbon nuclear re-ceptor translocator and binds to the hypoxia-responsive elements(HRE) on the gene encoding VEGF (Harris, 2002). Accordingly,Sharkeyetal.(2000)showedthatVEGFsecretionfromhypoxia-exposed endometrial stromal and glandular cel
45、l culturesmarkedly increases when compared withnormoxic cell cultures.Becker et al. (2008) reported that targeting the hypoxia mechanismrepresents another option to block VEGF signallingin endometriosis.In fact, they found that HIF-1a is up-regulated in surgically inducedperitoneal and mesenteric en
46、dometriotic lesions in mice, promotingtheincreasedexpressionofVEGF.Treatmentwith2-methoxyestradiol, an anti-angiogenic agent currently being tested inphaseII trialsfor cancer (Kulkeet al., 2011), dose-dependently inhibitsthisprocessandsuppresses lesiongrowth.Ofinterest,2-methoxyestradiol has minimal
47、 toxicities even upon administration ofhigh doses (Dahut et al., 2006). However, owing to its extensive?rst passmetabolism and low solubility, subtherapeutic plasma con-centrations of 2-methoxyestradiol have been observed despite largeorally administered doses (Verenich and Gerk, 2010). First, these
48、majorpharmacokinetic problemshave tobesolved before2-methoxyestradiol can successfullybe launchedinto the market.In light of the fact that endometriotic lesionsnot only expressVEGFbut also various other growth factors, it is obvious that the develop-ment of new blood vesselsin endometriotic lesions
49、is crucially de-pendent on the interaction of multiple signallingpathways (Fig. 3).To address this point, the effect of combined growth factor inhibitionon the vascularization of endometriotic lesions was analysed in thedorsal skinfold chamber of Syrian golden hamsters (Laschke et al.,2006a). This m
50、odel allows for the detailed analysisof angiogenesisand microvascular network morphology in endometriotic lesions bymeans of intravital ?uorescence microscopy (Laschke et al., 2005).Endometriotic lesions were treated with the small molecule tyrosinekinase inhibitorSU5416, which solely suppresses the
51、 activity ofVEGF receptor tyrosine kinase (Mendel et al., 2000), or SU6668,which is a multipotentinhibitor of the tyrosine kinase activity ofVEGF, basic ?broblast growth factor(bFGF) and platelet-derived684Laschke and Menger by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded fr
52、om growth factor receptors (Hoekman, 2001). Of interest, the combinedinhibition of all three growth factors was much more effective in sup-pressing lesion vascularization and growth than blockade of VEGFalone (Laschke et al., 2006a). These ?ndings indicate that anti-angiogeniccompounds, which target
53、 simultaneously different growthfactor signallingpathways,may be highly effective in the future anti-angiogenictherapy of endometriosis.EndogenousangiogenesisinhibitorsEndogenousinhibitors of angiogenesisareproteins or fragmentsof pro-teins,which are formed in the body andhavebeen shown to inhibit t
54、hedevelopment of new blood vessels(Nyberg et al., 2005). Manyof theseinhibitors are derived from extracellular matrix molecules, such asendostatin (Ribatti, 2009). This 2022kDa C-terminal fragment oftype XVIII collagen,which wasoriginallyisolatedandpuri?ed from con-ditioned media of murine hemangioe
55、ndothelioma cells (O Reilly et al.,1997), binds to aVb1integrin and E-selectin on endothelial cells andis a broad spectrum angiogenesisinhibitor, affectinghundreds of path-ways regulating the process of blood vessel development (Folkman,2006). Accordingly, endostatin inhibits the proliferation and m
56、igrationof endothelial cells and induces their apoptotic cell death (Dhanabalet al., 1999a, b). Moreover, endostatin suppressesmatrix metallopro-teinase (MMP)-2, -9 and -13 activity and blocks the binding of VEGFto its receptor (Kim et al., 2000, 2002). During the last years,severalindependent group
57、s demonstrated that treatment with endostatin orshort synthetic endostatinpeptidesinhibitsangiogenesisof newly devel-oping endometriotic lesions(Becker et al., 2005, 2006a, b; Nap et al.,2005; Jiang et al., 2007) and already established ones (Nap et al.,2004). Importantly, this type of treatment doe
58、s not interfere with fer-tility andpregnancyin mice(Beckeretal., 2005,2006a). Additional clin-icaldata indicatea favourabletoxicity pro?le of endostatin (Ederet al.,2002). In fact, endostatin has virtually no toxicity andhas revealednoproblems with resistanceeven during administration to patients ev
59、eryday for up to. 3.5 years without interruption(Folkman, 2006).However, a major prerequisite for the broad clinical applicability ofthisendogenous angiogenesis inhibitorinfutureendometriosistherapy is the synthesis of large quantities of pharmaceutical gradeprotein, which is still an unsolvedproble
60、m (Ribatti, 2009).Another endogenousinhibitor of angiogenesisis angiostatin, whichis a 38 kDa fragment of plasminogen (O Reilly et al., 1994; Ribatti,2009). Similar to endostatin, angiostatinaffects multiple mechanismsof blood vessel development. For instance, angiostatin has beenshown to suppresspr
61、oliferation andto induce apoptosis of the endo-thelium (Simet al., 2000). Moreover, it inhibitsVEGFand bFGFsignal-ling (Sim et al., 2000). The anti-angiogenic effects of angiostatin aremediated by its binding to various cell surface proteins, includingATP synthase, angiomotin, aVb3integrin, annexin
62、II, angiostatinbinding sequence protein, c-met and NG2 proteoglycan, as well asextracellular targets, such as tissue plasminogen activator (Wahlet al., 2005). Dabrosin et al. (2002) treated endometriotic lesions inestrogen-supplementedovariectomized mice by transient overexpres-sion of the angiostat
63、ingene,which wasdelivered to the peritoneum bya replica-de?cientadenovirusvector. Gene therapy mayovercome themajor problem that angiostatin has a short half-life in the circulationand, thus, a short interval dosing is necessaryto maintain its effectsunder clinical conditions (Beerepoot et al., 2003
64、; Wahl et al., 2005).However, although effective, this type of treatment impaired normalFigure2Flow diagram depicting selection of articles for review of studies focusingon the anti-angiogenic effect of different compounds on endo-metriosis, as listed in Table II.Anti-angiogenic therapy of endometri
65、osis685 by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from .TableIIStudies focusing on the anti-angiogeniceffect of differentcompoundson endometriosis.Substance groupStudyCompoundSpecies or cell culture/tissuetype/transplantationsiteAnti-angiogeniceffects on endometriosisG
66、rowth factorinhibitorsBecker et al. (2008)2-MethoxyestradiolC57BL/6 mice/mouse endometrium/peritoneal cavitySuppressionof HIF-1a and VEGFexpression,reduced vascularpermeabilityHull et al. (2003)Solubletruncated Flt-1 receptor,anti-VEGFantibodyNude mice/human endometrium/subcutisDisruption of immatur
67、e microvesselsLaschkeet al. (2006a)SU5416,SU6668Syriangoldenhamsters/hamster endometrium/dorsalskinfold chamberReduction of microvesseldensity,inhibition of vesselmaturationNap et al. (2004)Anti-VEGFantibodyNude mice/human endometrium/peritoneal cavityReduction of microvesseldensity,disruption of im
68、maturemicrovesselsNap et al. (2005)Anti-VEGFantibodyChicken/human endometrium/CAMassayReduction of microvesseldensityRein et al. (2010)VEGF-targetedgenetherapyCell culture/human endometriotic cellsInduction of apoptotic cell deathRicciet al. (2011)BevacizumabBALB/c mice/mouse endometrium/peritoneal
69、cavityReduction of microvesseldensity,decreaseof VEGFlevelsinperitoneal ?uidEndogenousangiogenesisinhibitorsBecker et al. (2005)Murine endostatinC57BL/6 mice/mouse endometrium/peritoneal cavityNo speci?canti-angiogeniceffectsreportedBecker et al. (2006a)Murine short synthetic endostatinpeptidesmP-1
70、and mP-6C57BL/6 mice/mouse endometrium/peritoneal cavitySuppressionof VEGF-inducedendothelial cell migrationBecker et al. (2006b)Murine short synthetic endostatinpeptide mP-1NOD-SCID or C57BL/6-Tyrcmice/mouse endometrium/peritoneal cavityInhibition of blood vesselsproutingDabrosin et al. (2002)Angio
71、statingenetherapyC57BL/6 mice/mouse endometrium/peritoneal cavityReduction of microvesseldensityJianget al. (2007)Recombinanthuman endostatinSCID mice/human endometrium/subcutisSuppressionof VEGFexpression,reduction of microvesseldensityNap et al. (2004)EndostatinNude mice/human endometrium/peritone
72、al cavityReduction of microvesseldensity,disruption of immaturemicrovesselsNap et al. (2005)EndostatinChicken/human endometrium/CAMassayReduction of microvesseldensityFumagillinanaloguesBecker et al. (2006b)CaplostatinNOD-SCID or C57BL/6-Tyrcmice/mouse endometrium/peritoneal cavityReduction of micro
73、vesseldensityBecker et al. (2011)Lodamin129S6/SvEvTacmice/mouse endometrium/peritonealcavityReduction of circulatingendothelial progenitor cellsNap et al. (2004)TNP-470Nude mice/human endometrium/peritoneal cavityReduction of microvesseldensity,disruption of immaturemicrovesselsNap et al. (2005)TNP-
74、470Chicken/human endometrium/CAMassayReduction of microvesseldensityStatinsBruner-Tran et al.(2009)SimvastatinNude mice/human endometrium/subcutisReduction of microvesseldensityCakmak et al. (2012)SimvastatinNude mice/human endometrium/peritoneal cavitySuppressionof MCP-1 expressionEsfandiariet al.
75、(2007)LovastatinFibrin culture system/human endometriumInhibition of vascularsproutingOktem et al. (2007)AtorvastatinWistar rats/rat endometrium/peritoneal cavityReduction of VEGFlevelsin peritoneal ?uidSharmaet al. (2010)AtorvastatinCellculture/human ectopic andeutopic endometrial stromalcellsReduc
76、tion of VEGF,RAGE,EN-RAGE and COX-2 expression686LaschkeandMengerbyguestonSept ember17,2014ht t p: / /humupd.oxfordj ournal s. org/Downl oadedf romCOX-2 inhibitorsDogan et al. (2004)RofecoxibWistar rats/rat endometrium/peritoneal cavityReduction of VEGFlevelsin peritoneal ?uidHull et al. (2005)Nimes
77、ulideNude mice/human endometrium/subcutisNo anti-angiogeniceffectLaschkeet al. (2007)NS398Syriangoldenhamsters/hamster endometrium/dorsalskinfold chamberReduction of microvesseldensityand VEGFexpressionMachado et al. (2010)ParecoxibSprague-Dawleyrats/rat endometrium/peritoneal cavityReduction of mic
78、rovesseldensity,decreasedexpressionof VEGFandFlk-1Olivares et al. (2011)CelecoxibBALB/c mice/mouse endometrium/peritoneal cavityReduction of vascularizedlesion areaOzawa et al. (2006)NS398SCID mice/human endometriotic tissue/peritoneal cavityReduction of microvesseldensityand VEGFexpressionPhytochem
79、icalcompoundsLaschkeet al. (2008)EGCGSyriangoldenhamsters/hamster endometrium/dorsalskinfold chamberReduction of microvesseldensityand blood perfusion, inhibition ofestrogen-stimulatedVEGFexpressionLaschkeet al. (2010)GenisteinSyriangoldenhamsters/hamster endometrium/dorsalskinfold chamberDelayed le
80、sion vascularizationLaschkeet al. (2011c)4-HydroxybenzylalcoholC57BL/6 mice/mouse endometrium/dorsalskinfoldchamberReduction of microvesseldensityRudzitis-Auth et al.(2012)XanthohumolBALB/c mice/mouse endometrium/peritoneal cavityReduction of microvesseldensity,inhibition of endothelial cellprolifer
81、ationWang etal. (2011)PuerarinChicken/human endometriotic tissue/CAM assayReduction of microvesseldensity,suppressionof MMP-9, ICAM-1and VEGFexpressionXu et al. (2009)EGCGSCID mice/human endometrium/subcutisReduction of microvesselsizeand density,decreaseof VEGF-AmRNAXu et al. (2011)EGCGSCID mice/hu
82、man endometrium/subcutisSuppressionof VEGF-C/VEGFR2signallingZhang et al. (2011)CurcuminWistar rats/rat endometrium/subcutisReduction of microvesseldensityand VEGFexpressionImmunomodulatorsLaschkeet al. (2006b)RapamycinSyriangoldenhamsters/hamster endometrium/dorsalskinfold chamberReduction of micro
83、vesseldensity,VEGFexpressionand endothelialcell proliferationVlahos et al. (2010)PentoxifyllineWistar rats/rat endometrium/peritoneal cavityDecreasedexpressionof VEGF-Cand Flk-1Xu et al. (2012)Lipoxin A4BALB/c mice/mouse endometrium/peritoneal cavityReducedactivity of MMP-9, decreasedmRNA levelsof V
84、EGFDopamine agonistsDelgado-Rosaset al.(2011)Quinagolide, cabergolineNude mice/human endometrium/peritoneal cavityReduction of microvesseldensityand angiogenicgene expressionGo mez et al. (2011)QuinagolideHumans/human endometriotic lesionsDown-regulation of VEGF/VEGFR2,CCL2, RUNX1, AGGF1 andPAI-1Nov
85、ella-Maestre et al.(2009)CabergolineNude mice/human endometrium/peritoneal cavityReduction of microvesseldensity,suppressionof VEGFand Notch-4expression,up-regulation of Ang-1 and WntNovella-Maestre et al.(2010)CabergolineNude mice/human endometrium/peritoneal cavityInhibition of VEGFand VEGFR-2expr
86、essionPPARagonistsHerington etal. (2011)PioglitazoneNude mice/human endometrium/peritoneal cavityReduction of microvesseldensityPeeterset al. (2005)RosiglitazoneCell culture/human transformed andprimary endometrialcellsSuppressionof VEGFexpressionOnalan et al. (2009)Feno?brateWistar rats/rat endomet
87、rium/peritoneal cavityReduction of VEGFlevelsin peritoneal ?uidProgestins,danazoland GnRH agonistsKatayamaet al. (2010)DienogestWistar rats/rat endometrium/dorsal skinfold chamberReduction ofmicrovesseldensityandblood perfusion, suppressionofblood vesselmaturationKhan et al. (2010)Leuprolide acetate
88、Humans/human endometriotic lesionsReduction of macrophagein?ltration and microvesseldensity,increaseof apoptotic cell deathMatalliotakis et al.(2003)DanazolHumans/serum samplesReduction of VEGFserum levelsMo nckedieck et al.(2009)Progesterone,dydrogesterone,dihydrodydrogesteroneNude mice/human endom
89、etrium/peritoneal cavitySuppressionof bFGF,VEGF-A,Cyr-61 andMMP expressionContinuedAnti-angiogenictherapyofendometriosis687byguestonSept ember17,2014ht t p: / /humupd.oxfordj ournal s. org/Downl oadedf romovarian function, as indicated by suppressedcorpus luteum develop-ment, decreased sex steroid p
90、roduction and reduced ovarian anduterine weight (Dabrosin et al., 2002). Thus,this therapeutic approachhasto be further optimized by controlled local or targeted delivery ofthe angiostaticgeneto minimize deleterious side effects on normal re-productive function.FumagillinanaloguesFumagillinis anatur
91、ally occurring antibiotic of Aspergillus fumigatuswithanti-angiogenic activity (Ingber et al., 1990). TNP-470 (formerlyAGM-1470) is a highly potent semisynthetic derivate of fumagillin,which targets methionine aminopeptidase-2, affects cell-cycleregula-tion through induction of p53 and p21WAF1/CIP1a
92、nd preventsVEGF-induced endothelial permeability, intercellular gap formationand ruf?e formation by suppression of Rac1 activation (Sin et al.,1997; Nahari et al., 2007; Benny et al., 2008). Since its discovery,TNP-470has been proved in various experimentaland clinicalstudies toact as an effective a
93、ngiogenesis inhibitorin differenttumour types (Kruger and Figg, 2000). In line with these studies,Nap et al. (2004, 2005) showed that TNP-470 impairs the formationof endometrioticlesions in the CAM assayand the nude mousemodel, which is associated with a decreased microvessel density oftheectopicend
94、ometrialtissue whencompared withcontrols.However, despite these promising results, TNP-470 is rather unsuit-able for the anti-angiogenictreatment of endometriosis in clinicalprac-tice becauseit exerts strong side effects on the female reproductiveorgans, including inhibition of endometrial maturatio
95、n and corporalutea formation as well as failure of embryonic growth during preg-nancy (Klauber et al., 1997). Another major drawback of TNP-470 is its neurotoxicity (Bhargavaet al., 1999). To overcome this,Satchi-Fainaroet al. (2004) synthesized a derivate of TNP-470, i.e.caplostatin,whichisconjugat
96、edtoawater-solublesyntheticN-(2-hydroxypropyl)methacrylamidecopolymer. Thus, it does notcross the blood brain barrier and exhibits a decreasedaccumulationin normal organs.Becker et al. (2006b) treated mouse endometrioticlesions with caplostatin and analysedtheir growth and vascularizationover time u
97、sing the non-invasive imaging technique of biolumines-cence. Notably, they found that caplostatin suppressesangiogenesiswithinthe lesions withoutexerting any general orspeci?c toxiceffects on reproductive function. Thus, this non-toxic fumagillin ana-loguemay bea candidate forfutureanti-angiogenic t
98、herapy.However,caplostatinshares themajorclinical limitationwithTNP-470 that it exhibits a poor oral availability and extremely ashort plasma half-life (Benny et al., 2008). Therefore, Benny et al.(2008) created lodamin by conjugating TNP-470 to an amphiphilicpolymer, which results in the assemblyof
99、 micelles in which the drugis enclosed and protectedfrom the acidic environment of thestomach. Ofinterest, Becker et al. (2011)recently foundthatlodamintreatmentofendometriosis-bearingmicesigni?cantlydecreases levels of circulating endothelial progenitor cells, whichhave been shown to act as major c
100、ontributors to the vascularizationof endometriotic lesions(Laschkeet al., 2011a, b).StatinsStatinsare a classof lipid-lowering drugs,which inhibit cholesterol syn-thesisby blocking 3-hydroxy-3-methylglutaryl-co-enzyme A reductase.TableIIContinuedSubstancegroupStudyCompoundSpeciesorcellculture/tissue
101、type/transplantationsiteAnti-angiogeniceffectsonendometriosisOtheragentsFengetal.(2012)QuinalizarinC57BL/6mice/mouseendometrium/dorsalskinfoldchamberReductionofvascularizedareaandmicrovesseldensityImeschetal.(2011)RomidepsinCellculture/humanimmortalizedepithelialendometrioticcellsInhibitionofVEGFgen
102、etranscription,proteinexpressionandsecretion,reductionofHIF-1aexpressionKrikunetal.(2010)ImmunoconjugatemoleculeIconNudemice/humanendometrium/peritonealcavityDisruptionoftissuefactor-expressingmicrovesselsNapetal.(2004)AnginexNudemice/humanendometrium/peritonealcavityReductionofmicrovesseldensity,di
103、sruptionofimmaturemicrovesselsNapetal.(2005)AnginexChicken/humanendometrium/CAMassayReductionofmicrovesseldensityAGGF1,angiogenicfactorwithGpatchandFHAdomains1;Ang-1,angiopoietin-1;bFGF,basic?broblastgrowthfactor;CAM,chorioallantoismembrane;CCL2,chemokineligand2;COX,cyclo-oxygenase;Cyr-61,cysteineri
104、chprotein61;EGCG,epigallocatechin-3-gallate;Flk-1,fetalliverkinase-1;Flt-1,fms-relatedtyrosinekinase1;HIF-1a,hypoxia-induciblefactor-1a;ICAM,intercellularadhesionmolecule1;MCP-1,monocytechemotacticprotein-1;MMP,matrixmetalloproteinase;NOD-SCID,non-obesediabetic-severecombinedimmunode?ciency;PAI-1,pl
105、asminogenactivatorinhibitor-1;RAGE,receptorforadvancedglycationendproducts;RUNX1,Runt-relatedtranscriptionfactor1;VEGF,vascularendothelialgrowthfactor.Thetablealsoliststhespeciesinwhichtheanalyseshavebeenperformed.Whereappropriate,additionalinformationisprovidedaboutthetypeoftissueusedandthetranspla
106、ntationsitefortheexperimentalinductionofendometrioticlesions.688Laschke and Menger by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from .TableIIISpeci?c targetsor mechanismsof action and reportedside effects of compounds,which have been shownto exertanti-angiogeniceffects on
107、endometriosis.SubstancegroupCompoundSpeci?c targets,mechanismsof actionSide effects reportedin experimental(E) and clinical (C) studiesGrowth factor inhibitorsAnti-VEGFantibody(? bevacizumab)Neutralization of active VEGF-A(Ferraraet al., 2005)Hypertension, proteinuria, impaired wound healing,gastroi
108、ntestinalperforation, thrombosis, bleeding(C) (Kambaand McDonald, 2007)2-MethoxyestradiolInhibitionof the expression,nuclearaccumulationandtranscriptional activityofHIF-1aInduction of apoptosisthrough activation of caspasecascadeInhibition of tubulin polymerizationby binding to the colchicinesite of
109、 tubulinInduction of endothelial nitric oxide synthase(Verenich andGerk, 2010)Hot ?ashes,fatigue,diarrhoea, nausea,hyperglycaemia,anaemia,oedema,thrombosis, elevationof liver transaminases(C) (Dahut et al.,2006)SU5416Selectiveinhibition of the tyrosine kinaseactivity of VEGFR-2(Mendel et al.,2000)He
110、adache,fatigue,nausea,vomiting,diarrhoea, pain, hyperglycaemia,elevated prothrombin time (C) (Fury et al., 2007)SU6668Inhibition of the tyrosine kinaseactivity of VEGFR-2,PDGFR-b, FGFR-1(Hoekman, 2001)Fatigue,nausea,vomiting, diarrhoea, pain,?u-like complaints, anorexia,changeof taste (C) (Kuenenet
111、al., 2005)EndogenousangiogenesisinhibitorsEndostatinBindingto avb1integrin andE-selectinPleiotropic action on hundredsof geneticpathways regulatingangiogenesisInhibition of endothelial cell proliferation and migrationInduction of endothelial cell apoptosisSuppressionof MMP-2, -9 and -13 activityBloc
112、kadeof VEGFsignalling(Kim etal., 2000, 2002; Folkman,2006)No toxic effectson fertility andpregnancy(E) (Becker et al., 2005, 2006a)No treatment-related side effects(C) (Ederet al.,2002; Folkman, 2006)AngiostatinBindingto ATP synthase,angiomotin, aVb3integrin, annexin II,angiostatinbindingsequencepro
113、tein, c-met and NG2 proteoglycan on the cell surfaceBindingto tissue plasminogenactivatorInhibition of endothelial cell proliferationInduction of endothelial cell apoptosisInhibition of VEGFand bFGFsignalling(Simet al., 2000; Wahl et al., 2005)Suppressionof ovarianfunction (E) (Dabrosin et al., 2002
114、)Erythemaat injection site, fatigue,nausea,deep venousthrombosis (C)(Beerepoot et al., 2003)FumagillinanaloguesTNP-470 (? AGM-1470)Inhibition of MetAP-2Induction of p53 and p21WAF1/CIP1Suppressionof Rac1activation (Sinet al., 1997; Nahari et al., 2007; Bennyetal., 2008)Inhibition of endometrial matu
115、ration and corpora luteaformation,embryotoxicity (E) (Klauberet al., 1997)Neurotoxicity, nausea,fatigue(C) (Bhargavaet al., 1999)CaplostatinSeeTNP-470No reported treatment-related side effects(E) (Satchi-Fainaro et al., 2004;Beckeret al., 2006b)LodaminSeeTNP-470No reported treatment-related side eff
116、ects(E) (Bennyet al., 2008; Beckeret al., 2011)StatinsAtorvastatin, Lovastatin,SimvastatinBlockadeof HMG-CoA reductaseInhibition of endothelial cell proliferationInduction of apoptosisby activation of the caspasecascadeDown-regulation of VEGFsynthesisSuppressionof MMP secretion (Dulak and Jo zkowicz
117、, 2005)No reported treatment-related side effectson reproductive function (E)(Oktem et al., 2007)Myopathy, diabetes mellitus, asymptomaticelevation of liver transaminases(C) (Mancini et al.,2011)COX-2 inhibitorsCelecoxib,Nimesulide, NS398,Parecoxib,RofecoxibInhibition of COX-2Inhibition of carbonic
118、anhydrasesInhibition of PDK1Induction of apotosisby inhibition of SERCA(Scho nthal, 2007)Cardiovascularevents(myocardialinfarction, stroke, thrombosis),hypertension,wound healingcomplications, renal failureor dysfunction,gastroduodenalulcers (C) (Becker,2005; Nussmeier et al.,2005; Solomonet al., 20
119、05)PhytochemicalcompoundsEGCGPleiotropic action on multiple molecular mechanismsincludingprotection ofDNA, inhibition of proteasome activity and geneexpression,induction ofapoptosis,cell-cycleregulation andcell proliferation (Chen et al., 2011)Anxiolytic activity, hypoglycaemicactivity, hepatotoxici
120、ty (E) (Mereles andHunstein, 2011)Nausea(C) (Chow et al., 2003)ContinuedAnti-angiogenictherapyofendometriosis689byguestonSept ember17,2014ht t p: / /humupd.oxfordj ournal s. org/Downl oadedf rom.TableIIIContinuedSubstance groupCompoundSpeci?c targets,mechanismsof actionSide effects reportedin experi
121、mental(E) and clinical(C) studiesCurcuminPleiotropic interaction with numerousmolecular targetsincludingtranscriptionfactors, growth factors, protein kinases,in?ammatory cytokines, enzymes,adhesionmoleculesand apoptosis-relatedproteins (Wilken et al., 2011;Zhouet al., 2011)No reported treatment-rela
122、ted sideeffects (E) (Zhang et al., 2011)No reported treatment-related sideeffects (C) (Wilken et al., 2011)PuerarinPleiotropic interaction with numerousmolecular targetsincludinggrowthfactors, anti-oxidative enzymes,MMPs, cell proliferation-related andapoptosis-relatedproteins (Liu et al., 2012)No r
123、eported treatment-related side effects (C) (Tanet al., 2008)GenisteinPleiotropic interaction with numerousmolecular targetsincludingtranscriptionfactors, growth factors, protein kinases,in?ammatory cytokines, enzymes,adhesionmoleculesand apoptosis-relatedproteins (Shanmugamet al., 2011)Genotoxicity,
124、 infertility, disruption of oestrous cyclicity andovarian function(E) (Stopper et al., 2005; Jeffersonet al.,2007)4-Hydroxybenzyl alcoholPleiotropic interaction with numerousmolecular targetsincludingcytoprotective genes,neurotrophic factors, growth factors, anti-oxidativeenzymes,MMPsandcell prolife
125、ration-related proteins (Descampset al., 2009;Laschkeet al., 2011c)No reported treatment-related sideeffects (E) (Descampset al., 2009;Laschkeetal., 2011c)XanthohumolPleiotropic action on numerouscellular mechanismsincludingproliferation,differentiation, apoptosis,in?ammationand angiogenesis(Gerhaus
126、eret al.,2002)No reported treatment-related sideeffects (E) (Dorn et al.,2010;Rudzitis-Authet al., 2012)ImmunomodulatorsRapamycinInhibition of mTORInhibition of VEGFsignalling(Guba et al., 2002)Anaemia,leukopenia,thrombozytopenia, hypercholesterolemia, arthralgias,oedema,impaired wound healing,pulmo
127、nary toxicity, angioedema,nephrotoxicity (C) (Buhaescuet al., 2006)Lipoxin A4Multiple anti-in?ammatory effects viaactivation of the FPR2/ALX receptorInhibition of VEGF-stimulatedangiogenesis(Bakeret al., 2009; Romano,2010;Hao et al.,2011)No adverseeffectson estradiol andprogesteronelevelsor oestrusc
128、ycling(E)(Xu et al., 2012)PentoxifyllinePleiotropic action on the production of in?ammatorymediators and theresponsivenessof immunocompetent cells to in?ammatorystimuliSuppressionof VEGFsignalling(Olive et al., 2004; Vlahos et al., 2010)Gastricdiscomfort, dizziness(C) (Olive et al., 2004)Dopamine ag
129、onistsCabergolineBindingto dopamine D2 receptorInhibition of VEGFR-2phosphorylationSuppressionof Notch-4, VEGFand VEGFR-2expressionUp-regulationof Ang-1 and Wnt (Gomez et al.,2006;Novella-Maestre et al.,2009)Cardiacvalveregurgitation,nausea,headache,dizziness, fatigue,constipation(C) (Webster et al.
130、,1992; Schadeet al., 2007)QuinagolideBindingto dopamine D2 receptorDown-regulation of VEGF/VEGFR-2,pro-angiogeniccytokines and PAI-1(Go mez et al., 2011)Nausea,headache(C)No teratogenic effects(C) (Barlier and Jaquet,2006)PPARagonistsFeno?brateBindingto PPAR- aPleiotropic action on multiple processe
131、sincludingenergyhomeostasis,metabolism, in?ammationand angiogenesis(Tyagiet al., 2011)Increaseof plasmacreatinine and homocysteine levels,myopathy,thrombosis, pulmonary embolism,pancreatitis(C) (Keech et al., 2005;Bouhlelet al., 2008)RosiglitazoneBindingto PPAR- gPleiotropic action on multiple proce
132、ssesincludingenergyhomeostasis,metabolism, in?ammationand angiogenesis(Tyagiet al., 2011)Myocardialinfarction, ?uidretention, weightgain,bone fractures(C) (NissenandWolski, 2007; Tolman, 2011)PioglitazoneSeerosiglitazoneUrinary bladder cancer,?uid retention, weight gain,bone fractures (C)(Tolman, 20
133、11; BalakumarandKathuria, 2012)690LaschkeandMengerbyguestonSept ember17,2014ht t p: / /humupd.oxfordj ournal s. org/Downl oadedf rom(Brautbar and Ballantyne,2011). They are widely used for the treat-ment of hypercholesterolemia and associatedcardiovasculardiseases.In addition, statins in high doses
134、have been shown to exhibit anti-angiogenic activity, mediated by multiple mechanisms including thesuppression of endothelial cell proliferation, induction of apoptoticcell death, down-regulation of VEGF synthesisand inhibition of MMPsecretion (Dulak and Jo zkowicz, 2005).Esfandiariet al. (2007) inve
135、stigatedthe effect of statins on cell pro-liferation and angiogenesisin a novel in vitromodel of endometriosis.For this purpose, human endometrial fragments were placed in athree-dimensional ?brin culture system andexposed to different con-centrations of lovastatin. Of interest, they could demonstra
136、te thatlovastatinalreadysuppressesvesselsprouting at the low concentrationof 1 mM, whereas cell proliferation is only inhibited at the higherconcentrationsof 510mM. Sharma et al. (2010)observedinatorvastatin-treated endometriotic stromal cells a signi?cantinhibitionof lipopolysaccharide-induced expr
137、ession of genes encoding angio-genic factors, including VEGF.Oktem et al. (2007) tested the in vivoeffect of atorvastatin in a rat model of surgically induced peritonealendometriosis. They found that a low atorvastatin dose of 0.5 mg/kg per day increasesthe size of endometriotic lesions, whereas hig
138、hdoses of 2.5 mg/kg per day cause their regressionand reduce VEGFlevels in the peritoneal ?uid of the animals.These are promising ?nd-ings,taking into account that much higher atorvastatin dosesof up to175 mg/kg do not show any adverseeffects on reproductive function(Oktem et al., 2007). In the nude
139、 mouse model, 5 and 25 mg/kg sim-vastatin effectively inhibits growth and vascularization of developingendometriotic lesions (Bruner-Tran et al., 2009) and suppressestheexpression of monocytechemotactic protein-1(Cakmak et al.,2012), which is known to stimulate the secretion of VEGFin endomet-rial s
140、tromal cells (Lin and Gu, 2005). Thereby, it should be mentionedthat the discrepancyin the chosen statin dosesin the described in vivostudies is related to the fact that atorvastatin is approximately two tofour times more potent than simvastatin (Bruner-Tran et al., 2009).Thisindicates that further
141、studiesare needed to identify the most suit-able statinsandtheir effectivedoses for the anti-angiogenictreatmentof endometriosis. In this context, it has to be consideredthat the rela-tivelyhighdoses,which are normally required to induce anti-angiogeniceffects, may increase the risk for typical side
142、 effects associated withstatin therapy, such as myopathies (Dulak and Jo zkowicz,2005;Manciniet al., 2011).Cyclo-oxygenase-2inhibitorsCyclo-oxygenases (COXs)are enzymes ofthe myeloperoxidasefamily, which catalysethe initial step of prostaglandin synthesisfromarachidonic acid(Smith et al.,1996).COX-1
143、is constitutivelyexpressed, whereasCOX-2istheinducibleisoformthatisup-regulated during in?ammatory and angiogenicprocesses,such astumour growth or in?ammatory bowel disease(Wang and Dubois,2010; Yao et al., 2011).Severalstudies report that COX-2 is also crucially involved in thepathogenesis of endom
144、etriosis. COX-2 over-expression is found inboth endometrioticlesions and eutopic endometriumof patientswith endometriosis when compared with controls (Ota et al., 2001;Matsuzakiet al., 2004a; Ceyhan et al., 2008; Horn et al., 2009; Choet al., 2010). Additionalexperimentalstudies demonstratethatProge
145、stins,danazolandGnRHagonistsProgesterone,dydrogesterone,dihydrodydrogesterone,dienogestBindingtosteroidhormonereceptors(Sitruk-Ware,2006;Mo nckediecketal.,2009)Breastpain,headache,acne,alopecia,migraine,weightgain,abnormalmenstrualbleedingpatterns,depression,decreasedlibido(C)(Guidaetal.,2010)Danazo
146、lInductionofanovulationIncreasingfreetestosterone(CanavanandRadosh,2000)Hirsutism,deependvoice,acne,?uidretention,weightgain,sweating,reductioninbreastsize,decreasedHDLandincreasedLDLcholesterol(C)(CanavanandRadosh,2000)LeuprolideacetateBindingtotheGnRHreceptor(Wilsonetal.,2007)Nausea,decreaseinbone
147、mineraldensity,decreasedlibido,depression,hot?ashes,insomnia,headache,weightgain(C)(Wilsonetal.,2007)OtheragentsAnginexMimickingofb-sheetdomainsofanti-angiogenicagents(Grif?oenetal.,2001)Noreportedtreatment-relatedsideeffects(E)(Dingsetal.,2003)RomidepsinInhibitionofHDACPleiotropicactionontumoursupp
148、ressorgenetranscription,cell-cycleregulation,apoptosis,angiogenesis(Coif?eretal.,2012)Infections,nausea,fatigue,thrombocytopenia,vomiting,diarrhoea(C)(Coif?eretal.,2012)QuinalizarinInhibitionofproteinkinaseCK2(Fengetal.,2012)UnknownImmunoconjugatemoleculeIconBindingtoaberranttissuefactor(Krikunetal.
149、,2010)Noadverseeffectsonfertility,noteratogenity(E)(Krikunetal.,2010)ATP,adenosintriphosphate;FGFR,?broblastgrowthfactorreceptor;HMG-CoA,3-hydroxy-3-methylglutaryl-co-enzymeA;MetAP-2,methionineaminopeptidase-2;mTOR,mammaliantargetofrapamycin;NG2,neuron-glialantigen2;PDGFR,platelet-derivedgrowthfacto
150、rreceptor;PDK1,3-phosphoinositide-dependentproteinkinase-1;PPAR,peroxisomeproliferator-activatedreceptor;Rac1,Ras-relatedC3botulinumtoxinsubstrate1;SERCA,sarcoplasmic/endoplasmaticreticulumcalciumATPase;VEGFR,vascularendothelialgrowthfactorreceptor.Anti-angiogenic therapy of endometriosis691 by gues
151、t on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from Figure3Angiogenic signallingpathways in endometriosis and speci?c targets of growth factor inhibitors, which have been shown to exert anti-angiogenic effects on endometrioticlesions, i.e. anti-VEGF antibody (? bevacizumab), 2-met
152、hoxyestradiol, SU5416 and SU6668. Under normoxia,HIF-1a is hydroxylated by proline hydroxylases following rapid VHL-dependent proteolysis (1). Under hypoxia, the proline hydroxylases are nolonger active. HIF-1 translocates to the nucleus, where it targets genes(via HRE) encoding multiple proteins, i
153、ncluding angiogenic growth factors(2). These growth factors are then secreted into the extracellular space where they bind to speci?c receptors located on the surface membraneof endothelial cells and pericytes (3). This leadsto the activation of various intracellular signallingpathways, which regula
154、te cell survival, proliferation,migration aswell asvascularpermeability (4). AKT, active human protein kinase;ERK,extracellular signal-regulatedkinase;FAK, focal adhesionkinase;FGF, ?broblast growth factor; FGFR,?broblast growth factor receptor; HIF, hypoxia-inducible factor; HRE, hypoxia-responsive
155、 elements; MAPK,mitogen-activated protein kinase; NOS,nitric oxide synthase; p300/CBP,p300/CREB-bindingprotein; PDGF, platelet-derivedgrowthfactor;PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase; PLCg, phospholipase Cg; RAS, rat sarcoma GTPase;Src, tyro-sine kinas
156、e; Ub, ubiquitin; VEGF,vascular endothelial growth factor; VEGFR,vascularendothelial growth factor receptor; VHL, von Hippel Lindauprotein.692Laschke and Menger by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from treatment with COX-2 inhibitors prevents the implantation of
157、endo-metrium to ectopic sites and induces the regression of establishedendometriotic lesions (Dogan et al., 2004; Matsuzaki et al., 2004b;Ozawa et al., 2006; Machado et al., 2010; Olivares et al., 2011).Theseresults can partly be explainedby the inhibition of angiogenesis.In fact, treatmentwith the
158、COX-2inhibitorNS398 signi?cantlydecreasesVEGFexpression and microvesseldensity in ectopic endo-metrial tissue in the dorsal skinfold chamber model (Laschkeet al.,2007; Fig. 4). Besides this anti-angiogenic effect, application ofNS398 further decreases the proliferation rate of endometrial cellsandin
159、duces their apoptotic cell death (Laschkeet al., 2007). Thus,in-hibition of COX-2 seemsto havebene?cialeffects on multiple cellularmechanisms,promoting the ?nalregression of endometriotic lesions.However, experimental studies indicate that this is not necessarilyachievedby each COX-2 inhibitor. Hull
160、 et al. (2005) reported thattreatment with nimesulide neither affects blood vessel developmentnor the number or sizeof endometriotic lesionsin the nude mousemodel. Whether theseresults arespeci?cfor nimesulideor alsotrans-ferable to other COX-2 inhibitors needsfurther clari?cationin appro-priate end
161、ometriosis models.Presently, non-speci?c COXinhibitors,such as Ibuprofen orAspirin, are already widely used for pain treatment in endometriosis(Ebert et al., 2005). In comparison, speci?c COX-2 inhibitors bearthe advantage that they exhibitmany fewer gastrointestinal sideeffects (FitzGerald and Patr
162、ono, 2001). A ?rst clinical trial indicatedthat they are also effective, safeand inexpensivein the managementof endometriosis-associatedpelvic pain (Cobellis et al., 2004). Consid-eringtheir additional anti-angiogenicaction, thesespeci?cCOX-2 inhi-bitors seem to be ideal for the treatment of endomet
163、riotic lesions.However, at the time of writing, COX-2 inhibitors have not beenapproved for endometriosis. This may be related to the fact thatthere are not enough clinical data availableabout their possible sideeffects on fertilityand pregnancy. In addition, COX-2inhibitors,such as rofecoxib and val
164、decoxib, have been withdrawn from themarket becauseof anexcessrisk of cardiovascularevents in long-termusers,including myocardial infarction, stroke and thrombosis (Becker,2005; Nussmeier et al., 2005; Solomon et al., 2005). Thus, althoughCOX-2 inhibitors may be a suitable component of the multimoda
165、lendometriosis therapy of the future, these compounds can only berecommended at present for short-term treatment of patients withsevere endometriosis, who are at low risk for cardiovascularevents,under clearly de?ned study conditions.PhytochemicalcompoundsThe demand for traditional medicine practice
166、sis rapidly risingin indus-trial countries (Wieser et al.,2007). Accordingly, anincreasingnumberof phytochemical compounds are presently analysedin terms of noveltherapeutic indications. This trend is driven by the hope that thesecompounds, of which many have already been used for thousandsof years
167、in traditional Chinese medicine, promote health and well-being, while minimizing toxicities and side effects.Among women with endometriosis, Chinese herbal medicine hasgainedpopularity asalternativepain therapy despite the lackof conclu-siveclinicalevidence(Cox et al., 2003;Wieser et al., 2007). Mor
168、eover,recent studies could identify severalphytochemical compounds whichinduce the regression of endometriotic lesions under experimentalconditions. These include epigallocatechin-3-gallate(EGCG; Laschkeet al., 2008; Xu et al., 2009, 2011), curcumin (Zhang et al., 2011),puerarin (Wang et al., 2011),
169、 genistein (Yavuz et al., 2007), 4-hydroxybenzyl alcohol (HBA; Laschkeet al., 2011c) andxanthohumol(Rudzitis-Auth et al., 2012). These compounds typically act as pleio-tropic agents,which in?uence multiple cellular mechanisms,such asproliferation, migration and apoptosis. Moreover, they inhibit the
170、de-velopment of new blood vesselsand, thus, can also be classi?edasanti-angiogenicagents.The polyphenol EGCG is the major chemical component of greentea (Yang et al., 2006). Using dosages of EGCG that have beenshown to be growth inhibitory in tumour studies, EGCG suppressesthe estrogen-stimulated ac
171、tivation, proliferation and VEGFexpressionof isolatedendometrial cells(Laschkeet al., 2008). In line with these invitro?ndings,EGCG further inhibits angiogenesisand blood perfusionFigure4Invivoanalysisof the anti-angiogeniceffect of the COX-2 inhibitor NS398 on developing endometriotic lesions,accor
172、ding to Laschkeet al.(2007). Endometriotic lesions (A and B, borders marked by dotted line) are induced by endometrial tissue transplantation into dorsal skinfold cham-bers of Syrian golden hamsters and analysed by intravital ?uorescence microscopy in blue-light epi-illumination with contrast enhanc
173、ement of themicrovasculature by iv application of 5% ?uorescein isothiocyanate-labelled dextran 150 000. Note that the lesion, which has been treated for 10days with the COX-2 inhibitor NS398, exhibits a markedly reduced microvessel density (B) when compared with the vehicle-treated control (A).This
174、 is associated with a decreased lesion size. Scalebars: 130 mm.Anti-angiogenic therapy of endometriosis693 by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from of endometriotic lesions without affecting the development of newblood vessels in ovarian follicles (Laschke et al.
175、, 2008). Xu et al.(2009) induced endometriotic lesions by transplantingeutopic endo-metriumfrompatientswithendometriosisintosubcutaneouspockets of severely compromised immunode?cient mice. Treatmentof these lesionswith EGCGover 2 weeks resulted in a reduced micro-vesselsize and density of the lesion
176、s and the adjacent tissues.In anadditional study by the samegroup, detailed angiogenesismicroarrayand pathway analyses revealed that this effect may be primarilymediated by the selectivesuppressionof the VEGF-C/VEGFR2signal-ling pathway (Xu et al., 2011).Curcumin is derived from the rhizome of the E
177、ast Indian plantCurcumalonga and is the major component of the spice turmeric(Wilken et al., 2011). In a recent study, Zhang et al. (2011) demon-strated that increasing curcumin doses of 50150mg/kg graduallyreduce the size of endometriotic lesions in rats, which is associatedwith a decreased microve
178、ssel density and VEGF expression of theectopic endometrial tissue. Consistent with the fact that curcuminhasbeen consumed asa dietary supplement for centuriesand is con-sidered pharmacologically safe (Wilken et al., 2011), the treatedanimalsdid not show anysignsof sideeffects during the 4-week treat
179、-ment period.Puerarin is derived from the Chinese medical herb Radixpuerariaeand belongsto the group of phytoestrogens,which exhibit a structuresimilar to 17b -estradiol (Hwang and Jeong,2008). Besidesestrogenicactivity, phytoestrogens can also have anti-estrogenic effects (Zhaoand Mu, 2011), which
180、makes them attractive for the treatment ofendometriosis. Accordingly, puerarin inhibits estrogen-stimulated vas-cularization of human endometriotictissue in the CAM assay bydown-regulation of MMP-9, intercellular adhesion molecule-1 andVEGFexpression (Wang et al., 2011). In contrast, genistein,anoth
181、erphytoestrogen isolated from soy products, only delaysthe angiogenicprocess during the initial establishment of endometriotic lesions indorsal skinfold chambers, but does not affect the ?nal vascularizationof the lesions (Laschkeet al., 2010).HBA is the pharmacological active component of Gastrodia
182、elataBlume , which is usedasatraditional herbal medicine for the treatmentof headache,tetanus and epilepsyowing to its analgesic,sedativeandanti-convulsant effects (Hsieh et al., 2000; Yu et al., 2005). Recently,HBA hasbeen shown to inhibit in vivovascularizationof endometrioticlesions,which were in
183、duced by endometrial tissuetransplantation intomouse dorsal skinfold chambers (Laschkeet al., 2011c). Additional invitroexperiments revealed that this may be related to the inhibition ofmultiple stepsof the angiogenicprocess,including expressionof angio-genic growth factors and MMPs,endothelial cell
184、 proliferation and mi-gration as well as vascularsprouting (Laschkeet al., 2011c).Xanthohumol is a prenylated ?avonoid isolated from hops, whichactsas a pleiotropic cancerchemopreventive agent (Gerhauser et al.,2002). Rudzitis-Auth et al. (2012) found that treatment with this com-pound effectivelyin
185、hibitsthe vascularizationandgrowth of endometrio-tic lesions, which are surgically induced in the peritoneal cavity ofBALB/c mice. Detailed immunohistochemical analysesshowed thatthis isassociatedwith areduced proliferating activityof the microvascu-lar endothelium in xanthohumol-treated lesions,whe
186、reasxanthohumoldoes not induce apoptotic death of endothelial cells. Moreover, thistype of treatment does not affect proliferation and vascularizationwithin the femalereproductive organs (Rudzitis-Auth et al., 2012).Taken together, these studies indicate that several phytochemicalcompounds maybe sui
187、tablefor the anti-angiogenictreatment of endo-metriosis. However, for this purpose most ofthese compounds wouldhave to be administered in doses which cannot be achievedby simpledietary consumption becauseof their low concentrations in medicinalherbs and their poor bioavailability.This problem may be
188、 overcomeby high-dose supplementation therapy because of recent progressinthe stereo-selective total synthesisof speci?ccompounds, asalreadydescribed for EGCG (Nagle et al., 2006). Another problem is thelack of clinical evidence for the ef?cacyof natural medicinal herbs orsynthetic phytochemical dru
189、gs in the treatment of endometriosis.Thus, there is a strong need for controlled clinical studies, whichhave to analyse the interaction of these compounds with otherdrugs and potential side effects in patients with endometriosis.ImmunomodulatorsDuring the last decades,numerous studieshaveshown that
190、abnormal-ities in the immune systemplay animportant role in the aetiology andpathogenesisof endometriosis, as previously reviewed in detail (PaulDmowski and Braun, 2004). Accordingly, immunomodulatory agentshave been suggested for the treatment of the disease. In line withthe fact that there is a cl
191、ose link between in?ammation and angiogen-esis (Fiedler and Augustin, 2006), some of these agents have beendescribed to exert speci?c anti-angiogenic effects on endometrioticlesions. These include lipoxin A4 (LXA4; Xu et al., 2012), rapamycin(Laschkeet al., 2006b) and pentoxifylline (Vlahos et al.,
192、2010).LXA4 is anendogenouseicosanoid, which isinvolved in the regula-tion of various in?ammatory processes(Romano,2010). Moreover, ithasbeen shown invitroand invivoto inhibit VEGF-stimulatedendothe-lial proliferation and angiogenesis(Baker et al., 2009; Hao et al., 2011).Of interest, both the endome
193、trium in experimental endometriosis inrats and the tissuesfrom patients with endometriosis show a higherexpression of LXA4 receptor when compared with normal tissues(Motohashi et al., 2005). For these reasons,Xu et al. (2012) recentlyanalysedfor the ?rst time the effect of LXA4 on angiogenesisin mou
194、seendometriotic lesions.They found that treatment with LXA4 inhibitsthe activity of MMP-9 and decreasesmRNA levelsof VEGF in endo-metrioticlesions, resulting in a signi?cant growth suppression andatrophy of their glands. However,the treatment does not alterserum estradiol and progesterone levels or
195、disrupt estrus cycling.Rapamycin(Sirolimus) is a mammaliantarget of rapamycin inhibitor,which is widely used asanimmunosuppressivedrug to prevent rejec-tion in organtransplantation (Buhaescuet al., 2006). Of interest, rapa-mycin in immunosuppressive doses has also been demonstrated toinhibit tumour
196、angiogenesisby decreasingVEGF production (Gubaet al., 2002). Basedon these results, the effect of rapamycinon endo-metriotic lesions was analysedin the dorsal skinfold chamber model(Laschkeet al., 2006b). Daily treatment of the lesions with 1.5 mg/kg rapamycin induced their regression,which was asso
197、ciatedwith aninhibition of VEGF-mediatedangiogenesis.In addition, rapamycin sup-pressed the proliferation of endometrial and endothelial cells. Thus,rapamycin also represents an effective inhibitor of angiogenesisinectopic endometrial tissue. Nonetheless, owing to its immunosup-pressive effect and r
198、isk pro?le it is questionable whether this com-poundwillmake itswayintoclinical endometriosistherapy(Buhaescuet al., 2006).694Laschke and Menger by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from In contrast, pentoxifylline hasalreadybeen tested in clinical trials asa pote
199、ntial drug for patients with endometriosis (Kamencic and Thiel,2008; Lu et al., 2012). Pentoxifyllineis a pleiotropic immunomodulat-ingagent, which in?uencesboth the production of in?ammatory med-iators, such as tumour necrosis factor-a, and the responsivenessofimmunocompetent cells to in?ammatory s
200、timuli (Olive et al., 2004).Recently, Vlahos et al. (2010) reported that pentoxifylline exerts ananti-angiogeniceffect on developing endometriotic lesions in rats bysuppressingVEGF-C and Flk-1 expression.Severalother experimentalstudies demonstrated the regression of endometriotic lesions underpento
201、xifylline treatment(Nothnicket al., 1994; Mohammadzadehet al., 2008). A major advantageof this drug is the fact that it doesnot inhibit ovulation and, thus, can be administered throughout thetime period of attempting conception (Olive et al., 2004). Moreover,pentoxifylline is well tolerated with onl
202、y minor side effects, such asgastric discomfort and dizziness (Olive et al., 2004). However, atthe time of writing there is still not enough clinical evidence tosupport the useof pentoxifylline in the managementof premenopausalwomen with endometriosis in terms of subfertility and relief of painoutco
203、mes (Lu et al., 2012).DopamineagonistsA decade ago, Basuet al. (2001) made the interesting discoverythatthe neurotransmitter dopamine selectivelyinhibitsthe vascularperme-abilizingand angiogenicactivity of VEGFat non-toxic levels,revealinganew link between the nervous systemand angiogenesis. This le
204、d to theideato usedopamine agonistsfor anti-angiogenictherapy.In gynaecol-ogy,dopamine agonists,suchascabergoline,are currently usedfor thesuppression of breast-feeding and treatment of hyperprolactinaemia(Gillam et al., 2006; Colao et al., 2007; Buhendwaet al., 2008). Im-portantly, cabergoline trea
205、tment during pregnancydoes not increasethe risk of spontaneousmiscarriage,premature delivery or congenitalabnormalities (Robert et al., 1996; Ricci et al., 2002).Basedon these reports, the Pellicer research group analysed theeffect of cabergoline on growth and vascularizationof endometrioticlesions
206、in the nude mouse model (Novella-Maestre et al., 2009).They found that daily oral treatment with cabergoline over 14 dayscausesthe regressionof endometriotic lesionsby suppression of cellproliferation and VEGF-mediated angiogenesis.They could furtherdemonstrate that cabergoline treatmentresults in a
207、 signi?cantlylower expression of VEGF and VEGFR-2 in endometrioticlesions(Novella-Maestre et al., 2010). Thus, they concluded that dopamineagonistsmay be successfulin the treatment of peritoneal endometri-osis. However, chronic cabergoline treatment is known to be asso-ciated with an increased incid
208、ence of cardiac valve regurgitation(Schadeet al., 2007). Therefore, in anadditional study they comparedthe ef?cacy of the non-ergot-derived dopamine agonist quinagolidewith that of cabergoline in inhibiting angiogenesisand vascularizationof endometriotic lesions (Delgado-Rosaset al., 2011). Becauseb
209、othcompounds were equally effective, they decided to perform a clinicalpilot study with quinagolide in hyperprolactinemic patients with endo-metriosis, who required a ?rst surgicalintervention and underwent asecond-look laparoscopy(Go mez et al., 2011). Of interest, treatmentwith the dopamine agonis
210、t quinagolide induced a 70% reduction ofendometrioticlesions, with35% of lesions vanishing completely.Further histological analysesrevealed that this was associatedwith adown-regulation of VEGF/VEGFR-2, pro-angiogenic cytokines andplasminogen activator inhibitor-1within the lesions. These highlyprom
211、ising results and the bene?cial side effect pro?le of quinagolidesuggestthat this compound should now be tested in larger clinicalmul-ticenter trials for its applicability in patients with endometriosis.Peroxisomeproliferator-activatedreceptoragonistsPeroxisomeproliferator-activatedreceptors(PPARs)a
212、religand-activated transcription factors, which compromise three sub-types, i.e. PPAR- a , PPAR- g and PPAR-b/ d (Tyagi et al., 2011).These nuclear receptors have a major regulatory function in energyhomeostasis, metabolic processes and in?ammation (Tyagi et al.,2011). Activation of PPAR-a reduces t
213、riglyceride levelsand activationof PPAR-b/ d enhances fatty acid metabolism and modulates the de-velopment of atherosclerosis.In contrast, PPAR- g activation mediatesinsulinsensitizationandenhancesglucosemetabolism. Accordingly, ef-fective PPAR agonists have been developed for the treatment ofhypert
214、rigliceridemia and type 2 diabetes mellitus in the form of ?bratesand thiazolidinediones (Lalloyer and Staels, 2010). Some of thesedrugs have been shown to inhibit the development of new bloodvessels,and, thus, may be usefulfor the treatment of angiogenicdis-eases(Biscetti et al., 2009).Onalan et al
215、. (2009) demonstrated for the ?rst time in a rat modelthat treatment with the PPAR- a agonist feno?brate causesregressionof endometriotic lesions,which is associatedwith reduced VEGFlevelsin the peritoneal ?uid. These results are rather surprising consideringthe fact that the peritoneal ?uid of pati
216、ents with endometriosis con-tains activators of PPAR- athat stimulate macrophage chemotaxis(Hornung et al., 2001). Peritoneal macrophages, in turn, are a majorsource of VEGF in endometriosis (McLaren et al., 1996). Thus,thesecontradictory?ndings indicatethatfurtherexperimentalstudies are needed to c
217、larify the exact role of PPAR- a in the patho-genesis of endometriosis and to identify potential applications ofPPAR-a agonistsin the treatment of the disease.In contrast, the effects of PPAR- g agonistson endometriosis havealready been extensively analysed under experimental conditionsduring the la
218、st few years. Severalrodent studies reported the regres-sion of endometriotic lesionstreated with a PPAR- g agonist(Lebovicet al., 2004; Demirturk et al., 2006; Aytan et al., 2007; Olivares et al.,2011). In addition, Lebovic et al. (2007) demonstrated in the baboonendometriosis model that the sizean
219、doverall number of endometrio-tic lesionsis signi?cantlyreduced in animalstreated with rosiglitazoneand pioglitazone (Lebovic et al., 2010) when compared with placebo-treated controls. These results may be caused by the pleiotropicaction of PPAR-g agonistson multiple cellular mechanisms. In fact,Kav
220、oussiet al. (2009) found that activation of PPAR-g inhibits the at-tachment of endometrial cells to peritoneal cells. Moreover, PPAR- gagonistshave been shown to suppressVEGFexpression in endomet-rial cells(Peeterset al., 2005) andto reduce the microvesseldensity indeveloping endometriotic lesions(H
221、erington et al., 2011).Taken together, these ?ndings indicate that PPAR- g agonistsarepromising drugs for the treatment of endometriosis. Accordingly,Moravek et al. (2009) published a ?rst case series of three womenwith endometriosis, who were recruited aspart of a prospective clin-ical trial and tr
222、eated with rosiglitazone for 6 months. They found thatAnti-angiogenic therapy of endometriosis695 by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from rosiglitazone was welltoleratedby thepatients and reducedendometriosis-induced pain in two patients, while one patient exper
223、i-enced no change. However,this clinical trial was not continuedbecauserosiglitazone was shown to causeanincreasedrisk of cardio-vascular side effects (Nissen and Wolski, 2007). Meanwhile, pioglita-zone hasalso been restricted in several countries, becausethe FDAwarned that it may cause cancer in th
224、e urinary bladder (Balakumarand Kathuria, 2012). These examplesclearly show that a major chal-lengefor the establishmentof PPAR-g agonistsin future endometriosistherapy is the identi?cation of drugs with an acceptable side-effectpro?le.Progestins,danazoland GnRHagonistsProgestins,danazol and GnRH ag
225、onistsare drugs which are alreadywidely used for endometriosis therapy because they reduce painsymptoms and effectively induce the regression of endometrioticlesions (Rodgers and Falcone, 2008). Noteworthy,several studiesreported that these drugs also exert anti-angiogenic effects besidestheir well-
226、known anti-hormonal activity.Dienogest, an orally active progestin with a favourable safetyandtolerability pro?le, has been shown to inhibit both embryonic andtumour cell-induced angiogenesis(Nakamura et al., 1999). In linewith these ?ndings, Katayamaet al. (2010) demonstrated in the ratdorsal skinf
227、old chamber model that dienogest treatment suppressesvascularizationof developing endometriotic lesions,as indicated by adecreased microvessel density and blood perfusion when comparedwith controls. Moreover, dienogest-treated lesionsexhibit a reducednumber of microvessels which stain positive for a
228、-smooth muscleactin. Thus,dienogestseemsto inhibit both the development and mat-uration of new blood vesselsin endometriotic lesions, which may con-tribute to its proven clinical ef?cacyin endometriosis treatment.Mo nckedieck et al. (2009) investigated the effect of progesterone,dydrogesterone and i
229、ts metabolite dihydrodydrogesterone on para-meters of extracellular matrix degradation and angiogenesisinvolvedin the development of endometrioticlesions in mice. Of interest,they found that these progestins suppressthe transcription of angio-genic growth factors, including bFGF, VEGF-A and Cyr61, a
230、nd ofMMPs to a different degree. Such differences may be used in thefuture to identify those progestins,or progestin combinations, whichare most effective in the treatment of endometriosis.Matalliotakis et al. (2003) analysed the soluble levels of differentgrowth factors and cytokines in the serum o
231、f patients with endomet-riosis andhealthy women. They could demonstrate that patients withendometriosis exhibited signi?cantly higher serum levels of VEGFwhen compared with controls. A 6-month treatment with the synthet-ic testosterone derivative danazol reduced these levels to a normalthreshold.Fin
232、ally,Khan et al. (2010) analysedbiopsy specimensfrom patientswith endometriosis, adenomyosis and uterine myoma, who weretreated for a variable period of 36months with the GnRH agonistleuprolide acetate. They could show that GnRH agonist treatmentdecreasesmacrophagein?ltration andmicrovesseldensity o
233、f endome-triotic lesions, which is associated with an increased apoptotic celldeath. Further studies now haveto clarify whether these observationsare related to the direct effect of leuprolide acetate on in?ammationand angiogenesis at thetissue level ortheindirecteffect ofhypoestrogenism. In fact, e
234、strogen has been shown toincreaseVEGF mRNA expression in endometrial cells (Shifren et al., 1996),which seemsto be directly mediatedby estrogenresponsesequencesin the VEGF gene(Hyder et al., 2000).OtheragentsIn addition to the above listed groups of different compounds, someagents havebeen shown in
235、individual reports to exert anti-angiogeniceffects in endometriosis. These include anginex (Nap et al., 2004,2005), romidepsin (Imesch et al., 2011), quinalizarin (Feng et al.,2012) and the immunoconjugate molecule Icon (Krikun et al., 2010).Anginex is a synthetic b-sheet-forming peptide, which has
236、beendesigned tomimicb-sheetdomains ofseveral anti-angiogenicagents, such as plateletfactor-4,interleukin-8 and bactericidal-permeability increasingprotein-1 (Grif?oen et al., 2001). Accordingly,anginex inhibits endothelial cell proliferation, adhesion and migrationand induces apoptosis in these cell
237、s (Grif?oen et al., 2001). In thecontext of endometriosis, anginexhasbeen demonstrated to suppressthe formation of endometrioticlesions in the CAM assayand toreduce the number of established lesions in the peritoneal cavity ofnude mice (Nap et al., 2004, 2005). However, anginex has not yetbeen teste
238、d in clinical studies and, thus, is not well characterized interms of potential side effects in humans.Romidepsin belongsto the group of histone deacetylase(HDAC)inhibitors, which in?uence gene expression by enhancingacetylationof histones in speci?c chromatin domains (Emanuele et al., 2008).HDAC in
239、hibitors are suggestedto be promising drugs for tumourtherapy because they exert potent anti-cancer activities, includingthe inhibition of angiogenesis(Emanuele et al., 2008). In a recentstudy, romidepsin has been shown to suppress the transcription, ex-pression and secretion of VEGF in human epithe
240、lial endometrioticcells (Imeschet al., 2011). This ?rst report indicates that HDAC inhi-bitors may also play a role in the future anti-angiogenictreatment ofendometriosis.Quinalizarin isa selectiveinhibitor of protein kinaseCK2, which is aserine/threoninekinase regulating a wide variety of biologica
241、l pro-cesses, including angiogenesis(Kramerov et al., 2008). Of interest,all three subunits of CK2 (a , aand b) are expressed in the stromaand glands of endometrial tissue and their activity is signi?cantlyreduced by quinalizarin(Fenget al., 2012). In line with these ?ndings,Feng et al. (2012) could
242、 demonstrate in the mouse dorsal skinfoldchambermodel of endometriosis that quinalizarininhibitsthe vascular-ization of endometriotic lesions, which is associatedwith their regres-sion. However, althoughthe animalstolerated the dailytreatment withquinalizarinwell in this study,it is currently unknow
243、n which sideeffectson which different organ systemsmay be induced by targeting CK2.Using an athymic mouse model of endometriosis, Krikun et al.(2010) demonstrated the anomalous expression of a tissue factor byendothelial cells in endometrioticlesions. Of interest, treatmentwith the immunoconjugate m
244、olecule Icon, which binds with high af?n-ity and speci?cityto this aberrant tissuefactor, largelydestroyed endo-metriotic lesions by vascular disruption. Importantly, the treatmentwith Icon did not interfere with subsequent fertility nor did it haveany teratogenic effects. Therefore, the authors con
245、cluded that Iconmay be anideal drug for women of reproductive agewho are sufferingfrom endometriosis and who desire subsequent fertility.696Laschke and Menger by guest on September 17, 2014http:/humupd.oxfordjournals.org/Downloaded from Potentialimpactofanti-angiogenictreatmentinfutureendometriosist
246、herapyNumerous compounds have been analysed during the last years interms of their anti-angiogenic activity in endometriosis. Typically,these compounds originally have been described as potential candi-datesfor anti-angiogeniccancer therapy but manyof their mechanismsof action are transferable to th
247、e treatment of endometriotic lesions.However, although cancer and endometriosis are similar in that theyare crucially dependent on angiogenesis,the safety requirements forananti-angiogenictherapy differ completely between the two entities.In fact, endometriosis is not a potentially life-threatening
248、disease,unlike cancer. Moreover, most of the affected patients are youngwomen in reproductive age,who desire to havechildren. Consideringthe fact that physiologicalangiogenesisis a major prerequisite for re-productive function (Reynolds et al., 1992), anti-angiogenic com-pounds have to target speci?
249、cally angiogenesisin endometrioticlesionsor, at least, should not exert long-term sideeffects on bloodvesseldevelopment within the ovary and uterus after stopping treat-ment. Accordingly, one of the major challengesin the future establish-ment of anti-angiogenic therapies is the detailed experimenta
250、l andclinical evaluation of their potential side effects in young women andtheir risk of teratogenity in case of pregnancy. Moreover, becausean anti-angiogenictherapy carries a high risk of impairing fertility, itmay primarily be used to treat patients suffering from severe painassociatedwith endome
251、triosis. For this purpose, promising candidatesfor therapy are, in particular, those anti-angiogeniccompounds whichhaveafavourablerisk pro?le and havealreadybeen clinicallyapprovedfor the safetreatment of other benign diseases.Furthermore, it should be considered that the development ofnew blood ves
252、sels in endometrioticlesions is not solely driven byone angiogenic growth factor but is most probably mediated byvarious angiogenic signalling pathways (Laschke et al., 2006a). Thismeansthat speci?c blockade of an individual factor may be compen-sated by redundant activity or up-regulation of other
253、factors. Toovercome this problem, the use of pleiotropic compounds, whichtarget simultaneously different mechanisms of blood vesseldevelop-ment, may be appropriate. Nonetheless, because of the heterogen-eity of endometriosis it is not likely that the application of any singleanti-angiogenic agent wi
254、ll be suf?cient to cure the disease. In fact,anti-angiogenic approaches typically induce theregression of anewly formedimmaturemicrovasculature butare notable todestroy maturepericyte-coveredblood vessels (Benjamin et al.,1999; Nap et al., 2004). Therefore,rectovaginal endometrioticlesions, which ar
255、e mainly composed of ?bromuscular tissue withmature microvessels (Itoga et al., 2003), may be resistant to anti-angiogenictherapy. On the other hand, anti-angiogenic compoundsmay effectively inhibitthe establishment of new endometrioticlesions with strong angiogenicactivity in early stagesof the dis
256、easeor after surgical treatment. Thus, they could gain major importancein the prevention or progression of endometriosis, contributing toa signi?cant reduction in the high recurrence rates associated withthe presently applied pharmacological and surgical treatment strat-egies. Moreover, the applicat
257、ion of anti-angiogenic compounds incombination with other well-established drugs may be important inthe development of novel therapeutic regimens for endometriosis,with fewer side effects and increased ef?cacy.ConclusionsAngiogenesisrepresents an integral part in the pathogenesisof endo-metriosis an
258、d various anti-angiogenicagentshave been proved in ex-perimental studies to induce the regression of endometriotic lesionsby targeting their blood supply. However, clinical evidencefor the ef-?cacy of anti-angiogenictreatment strategies in endometriosis is stilllacking.Thus, there is an urgent need
259、for controlled clinical trials totransfer the herein reportedexperimental ?ndings from bench tobedside. For this purpose, anti-angiogenic compounds have to beidenti?ed, which exhibit an acceptable spectrum ofside effectswithout affecting fertility or pregnancy in young women. If this suc-ceeds, anti
260、-angiogenictreatment strategies hold great promise as animportant component of future endometriosis therapy.Authors rolesM.W.L. designedthe study,identi?ed the articles,drafted and revisedthe manuscript. M.D.M. designed the study and revised the manu-script. Both authors approved the ?nal version of
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