Balkan Journal of Medical Genetics

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

INTRODUCTION

Endometriosis is defined as the presence of a functional endometrial layer with endometrial glands and stroma outside the uterine cavity. Dismenorhea, disparonea, pelvic pain and infertility are common symptoms. The incidence of the disease is 15.0-25.0% in reproductive age and it increases up to 20.0-40.0% in infertile women [1,2]. The morphologic appearance of endometriosis is marked by proliferation, infiltration and severe adhesions around the surrounding tissues. Research into its pathogenesis has focused on anatomic, hormonal, immunologic and genetic factors [3], although the etiopathology has not yet been clearly explained. However, endometriosis should be accepted as an estrogen- dependent condition because it is seen during the reproductive years and generally disappears after menopause. Conventional treatment modalities are based on deprivation of estrogen locally and systematically. Unfortunately, this treatment can have serious implications for fertility, and long-term treatment strategies cannot be applied because of side effects. Neovascularization is essential for survival and growth of exfoliated endometrium. Vascular endothelial growth factor (VEGF) is a heparin-binding angiogenic growth factor of 30 to 40 kd, a mediator of neovascularization. It increases vascular permeability and is needed for survival of newly formed blood vessels. Vascular endothelial growth factor is involved in both the cause and maintenance of peritoneal endometriosis [4]. The effect of the VEGF can be inhibited by receptor inhibition, VEGF receptor tyrosine kinase inhibition and monoclonal antibodies against VEGF. Bevacizumab is a recombinant humanized IgG1 antibody that binds to VEGF and terminates its biologic activity. It shows its activity in the tissue by inhibiting angiogenesis. The anti-VEGF effect of bevacizumab has been shown in many human cancers (5). Animal studies reveal that the decrease in tumor size is due to apoptosis which is caused by inhibition of angiogenesis [6-8]. This suggests that there is a close relationship between angiogenesis and apoptosis. Apoptosis is an important factor in etiopathogenesis of the endometriosis. There is a marked decrease in apoptosis levels in endometriotic women’s endometrial tissue compared with normal women. This difference is even shown in exfoliated endometrial tissue of endometriosis patients [9]. Apoptosis is regulated by pro-apoptotic and anti-apoptotic genes. The B cell lymphoma/leukemia 2 (Bcl-2) gene was first identified in follicular B cell lymphoma; up to now more than 20 Bcl-2 family member genes have been defined. These genes show their effects by inducing or inhibiting apoptosis. Bcl-2, B-cell lymphoma-extra large (Bcl-xl) are anti-apoptotic members and the Bcl-2-associated X protein (Bax) gene is a pro-apoptotic member [10]. Cytochromec is a mitochondrial protein that is released in case of mitochondrial damage and plays role in intrinsic pathway of apoptosis [11]. The aim of this study was to investigate the effects of anti-VEGF antibody Bevacizumab on endometrial explants, on adhesion formation and on apoptotic gene expression levels in the rat endometriosis model.

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