XXXX ( @entity19629 ), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of @entity1311 by modulating survival pathways in orthotopic models of metastatic @entity1 @entity43 .

@entity43 @entity1 @entity137 @entity19629 @entity19 @entity5 @entity843 @entity1311
Potential treatments for @entity43 that have become resistant to standard chemotherapies include modulators of @entity5 cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, @entity19629 , on @entity1 @entity43 cells, SKOV3ip1 and IGROV1, growing orthotopically in @entity19 . @entity19 with established disease were treated with vehicle (control), @entity1311 (weekly, intraperitoneal injections), @entity19629 (daily oral administrations), or a combination of @entity1311 and @entity19629 . Treatment with @entity1311 decreased @entity5 weight and volume of @entity843 . Combination therapy with @entity19629 and @entity1311 reduced @entity5 incidence and further reduced @entity5 weight and volume of @entity843 when compared with @entity1311 alone. @entity19629 alone occasionally reduced @entity5 weight but alone had no effect on @entity5 incidence or @entity843 . Immunohistochemical analyses revealed that treatment with @entity19629 and @entity19629 plus @entity1311 inhibited the phosphorylation of ETRs and suppressed the survival pathways of @entity5 cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of @entity19629 necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of @entity1311 . Treatment with @entity19629 enhanced the @entity137 mediated by @entity1311 as measured by the degree of apoptosis in @entity5 cells and @entity5 -associated endothelial cells. Collectively, these results show that administration of @entity19629 in combination with @entity1311 prevents the progression of @entity43 in the peritoneal cavity of @entity19 in part by inhibiting survival pathways of both @entity5 cells and @entity5 -associated endothelial cells.
