A NOVEL ANGIOGENESIS INHIBITOR BEVACIZUMAB
INDUCES APOPTOSIS IN THE RAT ENDOMETRIOSIS MODEL
Soysal D1,*, Kızıldağ S2,*, Saatlı B1, Posacı C1, Soysal S3, Koyuncuoğlu M4, Doğan ÖE1
*Corresponding Author: Sefa Kızıldağ, Ph.D., Dokuz Eylül University, Faculty of Medicine, 35340 İnciralti,
İzmir, Turkey. Tel.: +90-2324124613. Fax: +90-2322590541. E-mail:sefa.kizildag@deu.edu.tr
page: 73
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DISCUSSION
Treatment of endometriosis is based on surgical
excision of endometriotic foci and medical suppression
of ovarian steroid production. The choice of
treatment modality depends on factors including the
patient’s age, severity of symptoms, location and size
of the endometrial growth and fertility desire. Medical
therapy includes oral contraceptives, progestins,
and GnRH agonist, as well as androgen derivatives
[15]. Because of high recurrence rates and adverse
effect profiles, current treatment modalities are still
not fully satisfactory [16-19]. Novel agents and treatment
approaches are needed in order to improve our
ability to treat endometriosis lesions.
In a normal mileu of humans, vasculature is
maintained by the balanced presence of both pro angiogenic
and anti-angiogenic factors. Endometriosis
shifts the balance to favor angiogenic induction by
increasing expression of angiogenic inducers, decreasing
expression of angiogenic inhibitors, or a
combination of both. Histopathological examinations
reveal that angiogenesis is essential for survival and
development of endometriotic lesions [20-22] and maturity
of vessels in peritoneal lesion shows variations,
depending on the stage of endometriosis. In early endometriotic
lesions, high vascular density gives them
a red-pink color. Black lesions are seen in late stages
of disease and percentage of mature vessels is higher in those lesions [23,24]. This shows that maintenance
and growth of early endometriotic lesions depend on
newly formed blood vessels. Therefore, endometriosis
and cancer growth have many similarities. These
therapies cause a decrease in oxygen and nutrient supply
to tumor cells by reducing tumor vascular density,
perfusion and vascular permeability, which leads to
apoptosis of tumor cells. Anti-angiogenetic drugs,
which were used in many cancers, can be tried in endometriosis
models. In animal models, the inhibition
of endometriotic implant formation by blockage of
angiogenesis yield encouraging results, but in some of
them results were still unsatisfactory [25-30]. Vascular
endothelial growth factor is an important vasoactive
growth factor that plays a pivotal role in the regulation
of physiological and pathological angiogenesis. It has
been demonstrated that it is involved in pathophysiology
of endometriosis. Therefore, inhibition of VEGF
may be a potent therapeutic approach in treatment of
endometriosis.
The aim of this study was to reveal the effect of
bevacizumab, which is a VEGF antibody, on regression
of endometriotic explants. For this purpose we
have compared bevacizumab with GnRH agonist,
which is a well known treatment modality for endometriosis.
In this study, we observed that both GnRH
agonist and bevacizumab decrease the endometriotic
explants growth compared to the control group, but
there were no significant difference between GnRH
agonist and bevacizumab groups. Bevacizumab and
GnRH agonist both cause an induction in apoptotic
genes when compared with the control group, but no
significant difference was shown between bevacizumab
and GnRH agonist groups. The effect of growth
factor inhibition on endometriotic lesion regression
was first studied by Laschke et al. [29]. They found that
combined inhibition of VEGF, fibroblast growth factor
and platelet-derived growth factor cause decrease in
endometriotic lesion vascularization, but this effect
was not seen with only VEGF antagonization [29].
Recently, the efficacy of bevacizumab on endometriotic
lesion regression was studied by Ricci
et al. [31] in endometriosis mice models. In that
study, the induction of endometriosis was formed
with three equal pieces of endometrial tissue instead
of one piece and a control laparotomy (mice with
surgically-induced endometriosis were treated with
saline) for determination of explant viability was not
performed. Although they failed to show a decrease in
lesion numbers with bevacizumab, they demonstrated
a decrease in total lesion volumes, cell proliferation,
vascular density and an increase in apoptosis. However
this therapeutic effect of bevacizumab was not
compared with a known therapeutic modality [32].
At the present time GnRH agonist is one of the most
widely used treatment modalities for endometriosis
but can be used only for a limited time owing to unacceptable
side effects such as climacteric symptoms
and loss of bone density. As in many studies, our study
confirmed that GnRH agonist caused an increase in
apoptosis in endometrial cells besides hypoeustrogenic
state formation [32-36]. Meresman et al. [33]
also showed that GnRH agonist have a direct effect
in endometrial cells cultures, by enhancing the percentage
of apoptotic cells and decreasing the release
of angiogenic factors such as VEGF and interleuking
(IL)-1β. Moreover, Bilotas et al. [33] exposed that the
use of GnRH agonists enhance apoptosis in endometrial
epithelial cell cultures by increasing Bax and
FasL expressions and decreasing Bcl-2 expression.
Although the aim of our study was to evaluate
the effectiveness of bevacizumab in treatment
endometriosis, we found that bevacizumab caused
significantly less adhesion formation compared to
the control group, but we failed to demonstrate difference
between bevacizumab and GnRH agonist.
Moraloğlu et al. [37] studied the preventive effect of
bevacizumab on adhesion formation. In that study, a
rat uterine horn adhesion model was conducted and
high and low doses of bevacizumab treatments were
given. When compared with the control group, both
low and high doses of bevacizumab reduced adhesion
formation. Additionally, the high dose treatment did
better than the low dose treatment in prevention of
adhesion formation [37].
Bevacizumab was initially approved for the treatment
of metastatic colon cancer and other solid tumors.
It is important to note that treatment with bevacizumab
may have potential adverse effects such as proteinuria,
hypertension, thromboembolism and hemorrhages
[38]. However, it should be kept in mind that these
patients were mostly in terminal stage and were more
prone to these adverse effects. In our study, we did not
observe any adverse effect such as wound infection and
weight loss after administration of the drugs.
In conclusion angiogenesis and salvage from
apoptosis is required for development and maintenance
of endometriotic lesions. Up to now, this has been the first study to compare bevacizumab with
GnRH agonist. We observed that bevacizumab was
effective as leuprolide acetate in regression of endometriotic
lesions and caused less adhesion formation
compared to the control group. Polymerase chain
reaction studies revealed that a possible mechanism
of action of bevacizumab could be induction of apoptosis.
However, these observations are valid for rat
endometriosis models and further studies are required
in order to apply these observations to other species.
Declaration of Interest. This study was supported
in part by Dokuz Eylül University Research
Fund grant no. 2010.KB.SAG.042. The authors report
no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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