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

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 patientís 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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