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Microvascular Research 74 (2007) 121 130

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Angiogenesis and antiangiogenic therapy in endometriosis


Christian M. Becker a , Robert J. DAmato b,
a
Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, UK
b
Vascular Biology Program, Childrens Hospital Boston and Department of Ophthalmology, Harvard Medical School, 300 Longwood Ave, Boston, MA, USA

Received 14 March 2007; revised 25 April 2007; accepted 26 April 2007


Available online 6 May 2007

Abstract

Endometriosis, the presence of endometrium-like tissue outside of the uterine cavity, is a common disease among women of reproductive age.
Typical symptoms include abdominal pain and painful menstruation. In addition, endometriosis is associated with reduced fertility. Current
treatment modalities, the surgical removal of endometriotic lesions and the hormonal suppression of estrogen are associated with significant
morbidity, side-effects and recurrence rates. Despite uncertainties about the pathophysiology of the disease it has recently become apparent that
angiogenesis plays a pivotal role in endometriosis. This review focuses on a multitude of factors involved in the angiogenic phenotype of
endometriosis demonstrating that many biological systems such as the immune system and steroid hormones are closely connected to angiogenic
pathways in this disease. In addition, experimental and clinical data are discussed that concentrate on the inhibition of angiogenesis as a novel
therapeutic approach for endometriosis.
2007 Elsevier Inc. All rights reserved.

Keywords: Angiogenesis; Endometriosis; Angiogenesis inhibitors; Reproduction; Antiangiogenic therapy

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Angiogenic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
New therapies: angiogenesis inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Endostatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Angiostatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Anginex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
TNP-470 and caplostatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
VEGF inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
COX-2 and aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Corresponding author. Fax: +1 617 730 0231.


E-mail address: robert.damato@childrens.harvard.edu (R.J. DAmato).

0026-2862/$ - see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.mvr.2007.04.008
122 C.M. Becker, R.J. DAmato / Microvascular Research 74 (2007) 121130

Introduction large variation in angiogenic potential in mice, which is


genetically determined (Rohan et al., 2000). It is therefore an
Since the seminal paper by Judah Folkman in 1971, attractive hypothesis that only the women with high angiogenic
angiogenesis research has evolved into an important field in potential are able to support the growth of tissue resulting from
biology, and antiangiogenic therapy has become a significant retrograde menstruation and thus progress to get endometriosis.
treatment modality of cancer (Folkman, 1971). While the vast Regardless of the underlying pathophysiologic mechanism, it is
majority of angiogenesis research has focused on tumor studies, now well recognized that angiogenesis plays a key role in the
many other processes including age related macular degeneration establishment and growth of endometriotic lesions (Taylor et al.,
and psoriasis have also been identified to be angiogenesis 2002). Recent data suggest that the balance of local pro-
dependent (Folkman, 1995). Additionally, our laboratory showed antiangiogenic factors may determine whether endometriotic
the critical dependence of the female reproductive system on lesions develop and grow or not, a concept widely accepted in
angiogenesis for normal function (Klauber et al., 1997). tumor growth (Folkman, 1971). In fact, various pro- and
Interestingly, recent studies suggest that angiogenesis might antiangiogenic molecules have been identified in lesions and
play an important role in the pathogenesis of endometriosis peritoneal fluid of women (Laschke and Menger, in press). While
(Taylor et al., 2002). recent reviews have focused on angiogenesis in eutopic endome-
Endometriosis is defined as the presence of tissue resembling trium (Fraser and Lunn, 2000; Gargett and Rogers, 2001; Girling
endometrium in extra-uterine sites, most commonly the ovaries and and Rogers, 2005; Smith, 2001), we will concentrate here on the
peritoneum. Endometriosis is an estrogen driven disease and most prominent angiogenic factors in endometriosis and the
therefore affects almost exclusively women during their reproduc- interaction of the angiogenic pathway with other systems. Finally
tive years. Pelvic pain, painful menstrual periods and infertility are we will discuss the role of angiogenesis inhibitors in various animal
typical and often devastating symptoms (Berkley et al., 2005). The models of endometriosis and their therapeutic potential in humans.
prevalence of endometriosis in the general population is estimated
at approximately 1015%. However, in women undergoing Angiogenic factors
laparoscopic surgery to investigate the cause of their infertility or
pelvic pain, the rates are about 30% and 50% respectively Cytokines
(Kennedy et al., 2005). Identification of endometriotic lesions by
laparoscopy and, if possible, histological verification of endome- One of the main characteristics of endometriosis is its
trial glands and stromal cells are required to make the diagnosis. inflammatory nature. It has been shown that cytokines released
The main pathological processes associated with the disease are from immune cells play an important role in the pathogenesis of
peritoneal inflammation and fibrosis, and the formation of endometriosis (Vinatier et al., 1996). Many of these cytokines
adhesions and ovarian cysts. In addition, endometriosis has been possess angiogenic activity. At first, Oosterlynck et al. found that
associated with an increased risk of developing clear cell and peritoneal fluid of endometriosis patients had a stronger
endometrioid ovarian carcinoma (Prowse et al., 2006). angiogenic effect in the chicken chorioallantoic membrane
Different hypotheses on the pathogenesis of endometriosis (CAM) assay than peritoneal fluid from control women
exist, which may be supplementary to each other (Dunselman and (Oosterlynck et al., 1993). Peritoneal macrophages and activated
Groothuis, 2004). First, it is assumed that local or exogenous lymphocytes seem to play an integral role in the secretion of these
stimuli lead to metaplasia of the mesothelial cell layer of the proinflammatory/proangiogenic cytokines (Taylor et al., 1997).
peritoneal wall (Meyer, 1903). These metaplastic lesions are For example, interleukin-1 (IL-1) is produced by activated
believed to grow by acquiring blood supply after local invasion of macrophages in patients with endometriosis (Fakih et al., 1987)
the basement membrane. Secondly, Halban suggested that and results in the increased expression of vascular endothelial
endometriotic cells may be disseminated systemically through growth factor (VEGF) and interleukin-6 (IL-6) in vitro, possibly
the lymphatic or blood vessel systems (Halban, 1924). This theory due to an upregulation of its own receptor (Lebovic et al., 2000).
could explain the occurrence of endometriotic lesions at distant Furthermore, stimulation of endometrial stromal cells with IL-1
sites such as the lungs, skin, brain and eye. resulted in an upregulation of gene expression for IL-8, a cytokine
The other, more widely favored hypothesis, encompasses a with proangiogenic properties (Rossi et al., 2005).
phenomenon called retrograde menstruation (Sampson, 1927). It IL-8 is known to be a chemoattractant for lymphocytes and
is believed that viable endometrial cells and tissue reach the neutrophils, but lately has also been demonstrated to stimulate
abdomen through the Fallopian tubes at the time of menstruation, angiogenesis (Koch et al., 1992; Strieter et al., 1992). In
where they adhere to the peritoneal wall, invade the mesothelial endometriotic tissue Arici et al. showed that both the stromal
cell layer and basement membrane through enzymatic degrada- and the epithelial cells express IL-8 leading to invasion of
tion and provoke angiogenesis. However, invasion has only been neutrophils (Arici et al., 1993). When peritoneal fluid of
shown in animal models, but not in humans so far (Dunselman endometriosis patients was incubated with neutrophils, VEGF
and Groothuis, 2004). Also, retrograde menstruation is a common expression increased (Na et al., 2006). Incubation with IL-8 and
phenomenon occurring in more than 90% of women (Halme et al., TNF-alpha (TNF-) also resulted in increased expression of
1984). Therefore, further conditions must be in place to support VEGF, while neutralizing antibodies against IL-8 and TNF-
endometriotic growth. One determining factor might be the inhibited this reaction at least partially. However, there is still
angiogenic potential of individuals. Our laboratory has shown a some debate about the angiogenic role of IL-8 in endometriosis as
C.M. Becker, R.J. DAmato / Microvascular Research 74 (2007) 121130 123

in the CAM assay, angiogenic activity from peritoneal fluid of Koos, 1993; Lebovic et al., 2000; Lin et al., 2006; Shifren et al.,
patients with endometriosis was attributed to TNF- and not to 1996; Shweiki et al., 1992).
IL-8 or IL-1 (Maas et al., 2001). However, peritoneal fluid of VEGF is the most prominent and most studied proangiogenic
affected patients contains high IL-8 and TNF- levels (Rana et al., factor in endometriosis and it is widely believed that VEGF is the
1996), and IL-8 concentrations are elevated in fluid from main stimulus for angiogenesis and increased vessel permeability
endometriotic ovarian cysts compared to follicular cysts (Fasciani in this disease (Taylor et al., 2002). It has been shown that VEGF
et al., 2000). is strongly expressed by endometriotic lesions, activated macro-
IL-6 is another cytokine with angiogenic properties (Motro phages and neutrophils (McLaren et al., 1996; Mueller et al.,
et al., 1990). In a mouse model of endometriosis, IL-6 together 2000a; Shifren et al., 1996). Significantly increased VEGF levels
with tumor necrosis factor alpha (TNF-) was secreted by have been found in the peritoneal fluid and lesions of
macrophages and resulted in an upregulation of VEGF from endometriosis patients compared to controls or eutopic endome-
infiltrating neutrophils and macrophages (Lin et al., 2006). In trium, respectively (Donnez et al., 1998; McLaren et al., 1996).
addition, IL-6 expression is higher in endometriotic cysts and Donnez et al. discovered that red, highly active endometriotic
eutopic endometrium of patients with endometriosis compared to lesions contain the highest VEGF concentrations. However, in
eutopic endometrium of control patients (Tseng et al., 1996). menstrual effluent no difference in VEGF concentrations was
Monocytes/macrophages, which seem to play an important role in detected between endometriosis patients and controls (Malik
the pathogenesis of endometriosis, are also attracted by the et al., 2006). Thus, it was suggested that the elevated levels in the
cytokine RANTES (regulated on activation, normal T cell peritoneal fluid and endometriotic lesions were a secondary event
expressed and secreted), and RANTES concentration in the caused by an innate variation in systemic and local factors in
peritoneal fluid correlates with the extend of disease (Khorram women with endometriosis resulting in an abnormal peritoneal
et al., 1993). RANTES is expressed by endometrial stromal cells response to endometrial debris. However, the serum and urine
upon stimulation by TNF-, interferon- and IL-1 (Hornung VEGF levels in endometriosis patients do not seem to differ from
et al., 1997; Lebovic et al., 2001). Interestingly, Pritts et al. found normal controls (Gagne et al., 2003; Potlog-Nahari et al., 2004).
response elements for the transcription factor PPAR- (peroxi- Interestingly, various polymorphisms in the VEGF gene have
some proliferators-activated receptor ) on the RANTES been associated with an increased risk of endometriosis (Bhanoori
promoter and PPAR- ligands decreased the transcription and et al., 2005; Hsieh et al., 2004; Kim et al., 2005).
translation of RANTES in an in vitro model of endometriosis
(Pritts et al., 2002, 2003). PPAR- is known to have a direct effect Hormones
on endothelial cells. For example PPAR- ligands induce
endothelial cell apoptosis and down-regulate VEGF receptors Endometriosis is an estrogen driven disease. Estradiol is found
(Bishop-Bailey and Hla, 1999; Margeli et al., 2003). Therefore, in high concentrations in endometriotic lesions (Bulun et al., 2002).
PPAR- activation through specific ligands is expected to have an Estrogen is a potent stimulus of angiogenesis through a direct
inhibitory effect on angiogenesis. increase of VEGF expression (Hyder et al., 2000; Mueller et al.,
2000b). There are many pathways leading to the local accumulation
VEGF of estrogen in endometriosis (reviewed in Attar and Bulun, 2006),
many of which are also associated with angiogenesis. First, it was
Vascular endothelial growth factor is one of the most found that aromatase, the enzyme responsible for the conversion of
prominent and well-studied proangiogenic growth factors the C19 hormones androstenedione and testosterone into estrone
(Leung et al., 1989). Originally identified as vascular and estradiol, is upregulated in endometriotic lesions (Noble et al.,
permeability factor (VPF), VEGF is also a potent selective 1996). This upregulation was a result of a stimulation by
endothelial mitogen and survival factor, which delays or prostaglandins, in particular PGE2 (Noble et al., 1997). PGE2
reverses senescence of endothelial cells (Benjamin and Keshet, also has a direct effect on angiogenesis by enhancing VEGF
1997; Keck et al., 1989; Senger et al., 1986; Watanabe et al., expression (Pai et al., 2001). Prostaglandins are the product of
1997). VEGF or VEGF-A belongs to a family of dimeric enzymatic conversion of precursors such as arachidonic acid.
glycoproteins such as VEGF-B, -C, -D, -E and placenta growth Cyclooxygenase is the rate-limiting enzyme in this process leading
factor (PlGF). VEGF-A production is stimulated by cytokines, to the production of prostaglandin (PG)G2, which is then converted
hormones, growth factors and hypoxia. Its activity depends on into PGH2. In turn, the biologically active prostaglandins (e.g.
its binding to different receptors, such as VEGFR-1 (Flt-1), PGE2 and PGF2) are synthesized by specific prostaglandin
VEGFR-2 (Flk-1, KDR) and neuropillin-1 and -2. VEGF-A is synthases (Smyth et al., 2006). Cyclooxygenase-2 (COX-2) is
spliced to yield various isoforms with VEGF122, VEGF165 and upregulated in endometrium of patients with endometriosis
VEGF189 being the most prominent forms in humans (Dvorak, compared to controls and in endometriotic lesions themselves
2002). Given its potent angiogenic function, it has been leading to higher PGE2 levels required for aromatase and VEGF
proposed that inhibition of VEGF may be an attractive novel stimulation (Ota et al., 2001). VEGF itself is known to increase
therapeutic approach for the treatment of endometriosis (Taylor COX-2 expression at both transcriptional and post-transcriptional
and Mueller, 2004). VEGF expression is enhanced by various levels creating a positive feedback loop (Tamura et al., 2002; Wu
factors such as estrogen and progesterone, hypoxia, prostaglan- et al., 2002). In addition, IL-1, which is upregulated in
din E2, IL-1 and IL-6 (Ben-Av et al., 1995; Cullinan-Bove and endometriosis, has been demonstrated to stimulate COX-2 and
124 C.M. Becker, R.J. DAmato / Microvascular Research 74 (2007) 121130

PGE2 expression in endometrial stromal cells theoretically resulting (OReilly et al., 1997). Endothelial cell exposure to endostatin
in further stimulation of aromatase (Tamura et al., 2002). results in down-regulation of genes of angiogenic factors and
Another distinct factor leading to an accumulation of estradiol upregulation of other endogenous inhibitors (Abdollahi et al.,
in endometriotic lesions is an enzymatic defect in the enzyme 2004). Endostatin has been shown to act through various pathways
converting the weaker estrogen estrone into estradiol and vice on endothelial cells (see review in Tabruyn and Griffioen, 2007),
versa. 17 beta-hydroxysteroid dehydrogenase (17-HSD) is however specific effects of endostatin on the vasculature in
present in different tissues such as eutopic endometrium in two endometrium are unknown.
isoforms. The isoenzme 17-HSG type 2 responsible for the Endostatin suppresses endometrium-induced angiogenesis in
conversion of estradiol to estrone is significantly reduced, dys- the CAM assay (Nap et al., 2005). Our group has shown that both
functional or absent in endometriotic tissue leading to an accu- continuous and twice daily subcutaneous dosing of endostatin
mulation of estradiol (Zeitoun et al., 1998). inhibit the growth of endometriotic lesions in an autotransplanta-
tion mouse model (Becker et al., 2005). This treatment had a
New therapies: angiogenesis inhibitors significant effect in newly transplanted lesions, but did not
suppress growth in established lesions. However, Nap et al.
The initiation, extent and suppression of angiogenesis are highly demonstrated efficacy in established lesions in a murine model of
dependent on the balance between pro- and antiangiogenic factors. xenotransplanted human endometrium (Nap et al., 2004). Nap
In tumors, Hanahan and Folkman described this phenomenon as et al. showed that while control mice displayed immature blood
the angiogenic switch (Hanahan and Folkman, 1996). Recently, vessels, in endostatin treated mice only mature (-smooth muscle
molecules with antiangiogenic potential appear to be suppressed in actin positive) blood vessel remained. This concept of vascular
patients with endometriosis compared to controls. For example, normalization has also been demonstrated in tumors (Jain, 2005).
interferon gamma-induced protein 10 (IP10) concentrations are Each report used endometriosis models that differed in the type of
reduced in peritoneal fluid and adiponectin levels are reduced both endostatin used (murine versus human), the tissue (murine versus
in the peritoneal fluid and serum of endometriosis patients human), transplantation technique (loose surgical attachment
compared to controls (Takemura et al., 2005a,b; Yoshino et al., versus intraperitoneal insertion) and the mice used (immunocom-
2003). petent versus immunocompromised, respectively). This may
Recently, angiogenesis inhibitors have been approved for the account for the differences in the effects on established lesions. In
treatment of cancer and age related macular degeneration (Marx, future studies, genetic models of endometriosis may help identify
2005). Angiogenesis also plays a pivotal role in reproductive the effect of endostatin on angiogenesis in endometriotic lesions.
processes such as the cyclical changes of the endometrium, the Using the same model we were able to inhibit the growth of
creation and maintenance of a corpus luteum and embryonal and endometriotic lesions also by treatnent with a 27 amino acid peptide
fetal development. However, drugs with antiangiogenic potential of endostatin (Becker et al., 2006a). Importantly, we demonstrated
have been shown to cause detrimental effects on reproductive that both endostatin and endostatin peptides did not have any
functions both in animal models and in patients (DAmato et al., negative effects on reproduction and the offspring of treated
1994; Klauber et al., 1997; McBride, 1961). This may create pregnant mice. Endostatin has been in clinical studies previously
challenges for antiangiogenic therapy in patients of reproductive with a favorable toxicity profile (Eder et al., 2002). An almost
age. Therefore, it is imperative to completely understand the identical molecule (Endostar) is currently tested in phase III studies
angiogenic mechanisms involved both in normal and ectopic for cancer in China (Whitworth, 2006). Therefore, endostatin may
endometrium and to test angiogenesis inhibitors extensively in be a viable candidate to be tested in the clinic in the foreseeable
animal models for their safety profile before clinical studies can future.
commence in women with endometriosis.
Angiogenesis inhibitors can be divided into two distinct Angiostatin
groups: (i) drugs that sequester proangiogenic cytokines or inhibit
the interaction of cytokines with their cellular receptor; and (ii) Angiostatin is a proteolytic fragment of plasminogen and was
drugs, which have a direct inhibitory effect on the endothelial cells originally isolated from Lewis Lung carcinoma cells (OReilly
(Tabruyn and Griffioen, 2007). Importantly, an increasing number et al., 1994). Antiangiogenic properties have been associated with
of established drugs with often very different applications have the first four (angiostatin) or five kringle domains of plasminogen
been identified to have an antiangiogenic activity. As a result, (Cao et al., 1997; OReilly et al., 1994). Angiostatin acts directly on
these drugs are quicker to enter the clinical testing stage because activated endothelial cells by inhibition of ATPase activity of
of the already existing clinical experience. In the following, we endothelial cells (Veitonmaki et al., 2004), by activation of intrinsic
will review the present data and discuss possible other options in and extrinsic apoptosis pathways (Chen et al., 2006) and by
the future. interaction with surface ligands such as v3 (Wahl et al., 2005).
Angiostatin also inhibits permeability induced by VEGF, which is
Endostatin abundantly found in the peritoneal fluid of endometriosis patients
(McLaren et al., 1996; Satchi-Fainaro et al., 2005). Dabrosin et al.
The endogenous angiogenesis inhibitor endostatin is a proteo- demonstrated the inhibitory effect of angiostatin on endometriotic
lytic cleavage product from collagen XVIII. It was originally growth in a mouse model (Dabrosin et al., 2002). Peritoneal
isolated from conditioned media of hemangioendothelioma cells infection with replication-deficient adenovirus carrying the gene for
C.M. Becker, R.J. DAmato / Microvascular Research 74 (2007) 121130 125

angiostatin eradicated established endometriotic lesions in this 470 is known to target methionine aminopeptidase-2 (MetAP2)
model. Angiostatin also reduced the number of primary and (Griffith et al., 1997). Recently, Satchi-Fainaro et al. demonstrated
secondary follicles and corpora lutea. Estrogen levels were also that TNP-470 and the non-toxic N-(2-hydroxypropyl)metacryla-
decreased, but stayed within physiological levels. mide (HPMA) copolymer-linked TNP-470 inhibited VEGF
Adenoviral angiostatin (AdAng) therapy did not have a induced phosphorylation of its receptor (VEGFR2), rho activation
negative effect on endometrial cells in vivo and in vitro. Even and calcium influx (Satchi-Fainaro et al., 2005).
though no fertility experiments were performed it was suggested Nap et al. used TNP-470 systemically in their mouse and CAM
that this treatment would reduce the frequency of ovulation and, model for the treatment of endometriosis (Nap et al., 2005, 2004).
as such, possibly reduce the risk of developing ovarian cancer The drug reduced the number of established lesions by more than
(Gwinn et al., 1990). Expression of angiostatin was detected for 50% in mice and by 95% in the CAM model. In the chicken model
10 days in this model. By that time most lesions had been the vascular response was also significantly suppressed. Treat-
eradicated. Assuming that these results can be reproduced in ment of non-pregnant mice with TNP-470 (AGM1470) resulted
humans, one could speculate whether a single AdAng injection in inhibition of endometrial maturation and corpus luteum
would be able to eradicate all residual lesions after laparoscopic formation. In pregnant mice treatment with AGM1470 complete-
removal of endometriosis. With current hormonal or surgical ly inhibited embryonic growth by interfering with decidualiza-
treatments, recurrence of endometriosis is high (Miller et al., tion, placental and yolk sac formation and embryonic vascular
1998). It is expected that repeated injections of adenoviral vectors development (Klauber et al., 1997).
will result in an immune response leading to an increasingly Because of the dose limiting neurotoxicity and the negative
reduced yield of angiostatin levels. Therefore, other vectors may effects on reproductive processes, a non-toxic derivate of TNP-
be necessary for repeated therapy (Joki et al., 2001). However, as 470 was recently developed (Satchi-Fainaro et al., 2004). By
endometriosis often is a chronic disease this novel approach may linking the drug to a water-soluble polymer (HPMA), through a
offer the clinician another therapeutic tool once the hurdle of GlyPheLeuGly sequence, the molecule was increased
immune response is overcome. We have seen that direct injection significantly in size. This greatly reduces the penetration through
of angiostatin into macaque preovulatory follicles did not alter the blood brain barrier and subsequently diminishes TNPs
ovarian morphology nor had an effect on serum progesterone neurotoxicity. Because of the increased permeability in tumor
levels, suggesting that ovulation took place (Hazzard et al., 2002). vessels, the drug (caplostatin) is delivered selectively through the
In addition, in clinical phase I trials angiostatin was well tolerated hyperpermeable tumor vasculature while still preventing it from
(Beerepoot et al., 2003; Soff et al., 2005). crossing normal vessels (e.g. the blood brain barrier). Both TNP-
470 and caplostatin have been shown to inhibit vascular
Anginex permeability induced by VEGF (Satchi-Fainaro et al., 2005).
We have recently demonstrated that caplostatin inhibits
Anginex was designed to mimic numerous hydrophobic and endometriotic growth in a novel mouse model of endometriosis
cationic residues and a repeated anti-parallel -sheet structure, (Becker et al., 2006b). By transplanting transgenic, luciferase-
which are typical of some angiogenesis inhibitors (Griffioen et al., expressing endometrium into the peritoneum of wild-type mice we
2001). Anginex has been shown to inhibit proliferation, adhesion were able to monitor endometriotic growth, angiogenesis and the
and migration and trigger apoptosis of endothelial cells. In effect of antiangiogenic therapy in a non-invasive fashion.
addition, anginex inhibits the formation of endometriosis-like Intravenous injection of the substrate luciferin into these animals
lesions in the CAM assay (Nap et al., 2005) and reduces the resulted in bioluminescence approximately 3 days after transplan-
number of established endometriotic lesions in a mouse model of tation. Immunohistochemical staining in other models confirms our
endometriosis (Nap et al., 2004). In a murine tumor model, findings that new blood vessels can be found after this period
anginex did not shown any signs of toxicity as determined by suggesting that angiogenesis is occurring at that time (Eggermont
body weight, general behavior and appearance, histological et al., 2005; Grummer et al., 2001). Caplostatin delayed the onset of
evaluation of various organs as well as hematocrit and serum bioluminescence in our model suggesting an inhibitory effect on
creatinine levels (Dings et al., 2003; van der Schaft et al., 2002). angiogenesis, which led to a suppression of growth of endome-
However, anginex has not been used in clinical trials and no data triotic lesion. Importantly, we did not notice any general or specific
are available so far on the drugs effect on reproductive functions. toxic effects on reproductive function.

TNP-470 and caplostatin VEGF inhibition

The synthetic fumagillin analogue TNP-470 (AGM 1470) is a Recently, a humanized anti-VEGF antibody has been approved
potent angiogenesis inhibitor in vitro and has a broad anti-cancer for clinical use in metastatic colon cancer (Hurwitz et al., 2004). In
spectrum (Antoine et al., 1994; Folkman and Kalluri, 2003; addition, a 28-nucleotide RNA aptamer specific for the VEGF165
Ingber et al., 1990). In clinical trials of metastatic cancer, TNP- isoforms was introduced for the treatment of age-related macular
470 demonstrated efficacy as a single agent and in combination degeneration (Gragoudas et al., 2004). Other VEGF pathway-
with paclitaxel (Herbst et al., 2002; Kudelka et al., 1998). targeting molecules are currently used in clinical trials.
However, neurotoxicity was seen in patients at doses with anti- VEGF is increased in the peritoneal fluid of women with
tumor efficacy (Bhargava et al., 1999; Herbst et al., 2002). TNP- endometriosis (Donnez et al., 1998; McLaren et al., 1996) and a
126 C.M. Becker, R.J. DAmato / Microvascular Research 74 (2007) 121130

positive correlation between disease stage and VEGF concentration COX-2 and aromatase inhibitors
exists (Shifren et al., 1996). Hull et al. demonstrated in a mouse
model of endometriosis that systemic treatment with both a soluble Non-steroidal anti-inflammatory drugs (NSAIDs) and acet-
truncated receptor (sFlt-1) and an affinity-purified antibody against aminophen have distinct specificities for the three existing isoforms
VEGF significantly inhibited growth of endometriotic lesions (Hull of the enzyme cyclooxygenase (COX-1, -2 and -3) accounting for a
et al., 2003). Therapy of the mice with these agents resulted in different spectrum of actions and side-effects. Most NSAIDs act as
disruption of pericyte-free, immature vessels, which resembles data non-selective inhibitors of COX-1 and -2 and are almost equally
from tumor studies (Bergers et al., 2003). In the studies by Nap effective clinically when used at equivalent doses (Fields and
et al., treatment with an anti-VEGF antibody showed similar results Martin, 2005). However, specific COX-2 inhibitors have been
(Nap et al., 2005, 2004). Laschke et al. recently used a dorsal skin identified (Masferrer et al., 1994) and COX-2 inhibitors have been
fold chamber model in hamsters to investigate the effect of small demonstrated to inhibit angiogenesis in tumor models (Masferrer
molecule inhibitors on angiogenesis in endometriosis (Laschke et al., 2000). It was originally believed that these specific COX-2
et al., 2006b). The authors found that the VEGF-selective drug inhibitors would be associated with fewer side-effects, especially in
SU5416 was inferior to SU6668, which has a wider spectrum the gastrointestinal tract. However, recent data suggesting increased
(VEGF, FGF (fibroblast growth factor), PDGF (platelet-derived cardiovascular morbidity and mortality in elderly patients taking
growth factor)), suggesting that a broader approach may be more COX-2 inhibitors have led to tough restrictions and the removal of
successful. In the same model, the group found that rapamycin, an some drugs from the market (Couzin, 2004a,b).
antifungal and immunosuppressive drug, inhibits endometriotic COX-2 is upregulated in endometrium of patients with
growth and VEGF-induced angiogenesis (Laschke et al., 2006a). endometriosis compared to controls and in endometriotic lesions
Hypoxia is one of the most potent stimuli of VEGF expression themselves (Ota et al., 2001). Peritoneal macrophages of
(Shweiki et al., 1992). Under hypoxic conditions, hypoxia endometriosis patients expressed higher COX-2 levels compared
inducible factor-1 alpha (HIF-1), which is degraded in normoxic to controls (Wu et al., 2002). Interestingly, no difference was seen
conditions, escapes ubiquitination, and translocates into the nucleus in monocytes purified from blood in the two groups. Fagotti et al.
where it binds HIF-1/ARNT (aryl hydrocarbon nuclear receptor found the strongest expression of COX-2 in the walls of
translocator) (Wang et al., 1995; Wang and Semenza, 1993). The endometriotic cysts (78%) compared to peritoneal lesions
HIF-1/HIF-1/ARNT complex then binds to hypoxia responsive (11.1%) and rectovaginal nodules (13.3%) (Fagotti et al., 2004).
elements on various genes including VEGF. We have recently Specific inhibitors of COX-2 have been successfully used for the
shown that HIF-1 is upregulated in endometriotic lesions in a treatment of endometriosis-associated pain (Cobellis et al., 2004).
mouse model, resulting in increased expression of VEGF In rodent models, selective COX-2 inhibitors were able to
(manuscript in review). Interestingly, treatment of endometriosis suppress establishment and growth of endometriotic lesions
bearing mice with the angiogenesis inhibitor 2-methoxyestradiol (Dogan et al., 2004; Matsuzaki et al., 2004; Ozawa et al., 2006).
resulted in down-regulation of HIF-1 and consequently in VEGF. The effect seen may depend on the model and drug used since the
In addition, oral treatment with 2-methoxyestradiol inhibited specific COX-2 inhibitor nimesulide did not regress lesions
endometriotic growth in a dose-dependent manner (manuscript in number, size, blood vessel density or macrophage infiltration into
review). human endometriotic lesions in nude mice (Hull et al., 2005).
Recently, it was shown in a Syrian hamster skinfold chamber
Thiazolidinediones model that the selective COX-2 inhibitor NS398 inhibited growth
of autologous endometrial grafts via inhibition of angiogenesis
Thiazolidinediones are artificial ligands of PPARs. PPAR- (Laschke et al., 2007). Daily systemic treatment led to inhibition
and - are expressed by peritoneal macrophages isolated from of VEGF expression, reduced proliferation and activation of
endometriosis patients (Hornung et al., 2001). The PPAR- apoptosis resulting in reduced vascular density in the lesions.
ligand rosiglitazone has been shown to inhibit angiogenesis in As with all drugs that are used in women it is important to
tumors (Panigrahy et al., 2002). In human endometrial cells evaluate the effect on reproductive functions. Inhibition of COX-2,
rosiglitazone suppressed the expression of VEGF (Peeters et al., which is upregulated during follicular development, is associated
2005). In a rat model of endometriosis systemic treatment with with reduced fertility due to suppression of ovulation (luteinized
rosiglitazone suppressed establishment and growth of autotrans- unruptured follicle (LUF) syndrome) (Killick and Elstein, 1987;
planted lesions (Demirturk et al., 2006). Thiazolidinediones are Stone et al., 2002). In COX-2 knock-out mice the effects on female
insulin sensitizers and thus used clinically as anti-diabetic drugs. reproductive function are more severe compared to pharmacologic
Clinical studies in patients with polycystic ovarian syndrome inhibition of COX-2 (Reese et al., 2001). However, our group
(PCOS) indicate increased fertility rates (Rouzi and Ardawi, demonstrated that the selective COX-2 inhibitor celecoxib did not
2006). Rosiglitazone did not have any negative effects on have a negative effect on the estrous cycle in mice, while inhibiting
reproduction and offspring in a mouse model (Klinkner et al., growth of endometriotic lesions suggesting that an intrinsic lack of
2006). However, no clinical data on the treatment of endometri- COX-2 may have different effects than drug-induced inhibition of
osis with rosiglitazone or any of the other thiazolidinediones are the enzyme (Efstathiou et al., 2005). It is conceivable that the side-
currently available. Still, the fact that the thiazolidinediones are effect profile differs between various drugs.
established drugs in the clinic makes them attractive candidates Bulun et al. have developed a model illustrating the interaction
for use in clinical trials in endometriosis patients in the future. of various hormones and enzymes including COX-2 (Attar and
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Beerepoot, L.V., et al., 2003. Recombinant human angiostatin by twice-daily
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