Effects of Pazopanib, Sunitinib, and Sorafenib, Anti-VEGF Agents, on the Growth of Experimental Endometriosis in Rats

Abstract

We aimed to compare the effects of pazopanib, sunitinib, and sorafenib on endometriotic tissue morphology and histological characteristics as well as ovarian reserve in a rat model. Experimental endometriosis was established in 32 rats. They were randomly divided into 4 groups (8 rats for each group) to administer study drugs: pazopanib, sunitinib, sorafenib, and normal saline. Histological examination with hematoxylin and eosin staining to determine endometriosis score and immunostaining with primary vascular endothelial growth factor (VEGF), CD117, and Bax antibodies were performed. Bilateral ovaries excised to determine the ovarian follicle number. The endometriosis score was significantly reduced by pazopanib compared to other study drugs and by sunitinib compared to sorafenib and normal saline (P < .05). Sorafenib did not affect endometriosis score (P > .05). The VEGF score was significantly decreased similarly by pazopanib, sunitinib, and sorafenib compared to normal saline (P < .05). The CD117 score was reduced by pazopanib and sunitinib similarly compared to both sorafenib and normal saline that provided similar effect on the score (P < .05). The Bax scores of all the groups were found similar (P > .05). No study drugs caused meaningful change in the ovarian follicle number (P > .05). Pazopanib reduces the growth of endometriotic implants. This effect may be related to the suppressive effect of pazopanib on the endometriotic tissue expressions of VEGF and CD117 but not Bax. The study drugs do not affect ovarian reserve. The inconsistent effects of study drugs regarding study parameters require further studies to elucidate the molecular bases of their effects on the growth of endometriotic implants.

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis

“…We screened the 135 full publications and excluded an additional 122 publications for the following reasons: 54 combined anti-angiogenesis therapy effects; 13 were cell studies; 4 duplicate publications; 37 reviews; 4 with no relevant outcomes; 8 were not relevant to endometriosis; 1 model was significantly different from the other studies; and 1 had no obtainable concrete data. Finally, the present systematic review included 13 articles comprising 16 animal experiments with 245 animals, published between January 1995 and June 2016, which met the inclusion criteria [16–28] (Table 1). The characteristics among these studies varied considerably.…”

“…Endometriosis score outcomes after anti-VEGF/VEGFR therapy were reported in 9 experiments [20, 22, 23, 26–28]. Taken together, these experiments showed that anti-angiogenesis intervention was associated with a lower endometriosis score (SMD –1.17, 95% CI –1.65 to –0.69; P < 0.0001) with a large heterogeneity in the estimates (I 2 = 50.3%, 95% CI 0% to 77%; H 2 = 1.01; Fig 2D).…”

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

“…Sunitinib was able to decrease the endometriotic implant volume and adhesion level in an experimental animal model, presumably by inhibiting VEGFR and enhancing apoptosis [159,163]. When various multitargeted TKIs were compared, each seemed to have a different effect on endometriosis extent, VEGF expression, and CD117 expression [164]. Pazopanib and sunitinib significantly reduced endometriotic lesions, whereas sorafenib had no significant effect [164].…”

“…When various multitargeted TKIs were compared, each seemed to have a different effect on endometriosis extent, VEGF expression, and CD117 expression [164]. Pazopanib and sunitinib significantly reduced endometriotic lesions, whereas sorafenib had no significant effect [164]. Three drugs (pazopanib, sunitinib, and sorafenib) reduced VEGF expression but only pazopanib and sunitinib reduced CD117 expression [164].…”

“…Pazopanib and sunitinib significantly reduced endometriotic lesions, whereas sorafenib had no significant effect [164]. Three drugs (pazopanib, sunitinib, and sorafenib) reduced VEGF expression but only pazopanib and sunitinib reduced CD117 expression [164]. Studies published to date have found no negative effects of these drugs on ovarian reserve, but further studies are necessary to assess the immune profile after drug administration and delineate the differential applicability of TKIs for enhanced infertility treatment [165].…”