Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancer

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Publisher: NRC Research Press
Document Type: Report
Length: 3,977 words

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Abstract :

In human ovarian carcinoma, the endothelin-1 (ET-1)/endothelin A receptor ([ET.sub.A]R) axis is overexpressed, correlating with tumor grade. Moreover, [ET.sub.A]R activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. [ET.sub.A]R blockade with zibotentan (ZD4054), a specific ETaR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and laxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials. Key words: ovarian cancer, ET-1, [ET.sub.A] receptor, zibotentan, combination therapy. Dans le carcinome ovarien humain, l'axe endotheline-1 (ET-1)/recepteur A de l'ET ([RET.sub.A]) est surexprime, en relation avec le grade tumoral. De plus, l'activation du [RET.sub.A] par l'ET-1 entraine de nombreux effets cellulaires, y compris la proliferation, la survie, l'angiogenese et l'invasion. Le blocage du RETA au moyen du zibotentan (ZD4054), antagoniste specifique de [RET.sub.A], inhibe significativement la croissance du cancer ovarien in vitro et in vivo, soulignant l'interet de cette voie comme cible dans le traitement du cancer. Les resultats d'essais cliniques ayant defini l'association platine-taxane comme une norme de soins dans le traitement du cancer ovarien, nous avons examine l'efficacite therapeutique de l'association de zibotentan et de medicaments cytotoxiques ayant differents modes d'action. Nous avons constate que l'association zibotentan-cisplatine et zibotentan-paclitaxel inhibe plus efficacement la proliferation des cellules HEY de carcinome ovarien induite par l'ET-1 endogene que l'emploi de medicaments seuls. Toutefois, l'efficacite a augmente de maniere significative lorsque nous avons combine zibotentan, cisplatine et paclitaxel. Ainsi, dans les xenogreffes de cellules HEY, la coadministration de zibotentan et de cisplatine a stimule l'efficacite du medicament cylotoxique pour controler la croissance de la tumeur, comme indique par la diminution de l'index de proliferation et de la densite des microvaisseaux. L'association zibolenlan- eisplalinepaclilaxel a ete tres efficace pour inhiber la croissance tumorale, la neovascularisation et la proliferation cellulaire, et represente un critere preclinique pour guider la polytherapie dans les essais cliniques. Mots-cles : cancer ovarien, ET-1, recepteur [ET.sub.A], zibolentan, polytherapie. [Traduit par la Redaction]

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Gale Document Number: GALE|A231994930