In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1alpha target genes and decreases tumor angiogenesis.
Fiche publication
Date publication
janvier 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BACHELLIER Philippe, Dr GUENOT Dominique, Dr GUERIN Eric, Dr MORAS Dino, Pr OUDET Pierre, Dr PENCREACH Erwan, Dr POCH Olivier, Dr RAFFELSBERGER Wolfgang, Pr ROHR Serge
Tous les auteurs :
Guerin E, Raffelsberger W, Pencreach E, Maier A, Neuville A, Schneider A, Bachellier P, Rohr S, Petitprez A, Poch O, Moras D, Oudet P, Larsen AK, Gaub MP, Guenot D
Lien Pubmed
Résumé
Topoisomerase I is a privileged target for widely used anticancer agents such as irinotecan. Although these drugs are classically considered to be DNA-damaging agents, increasing evidence suggests that they might also influence the tumor environment. This study evaluates in vivo cellular and molecular modifications induced by irinotecan, a topoisomerase I-directed agent, in patient-derived colon tumors subcutaneously implanted in athymic nude mice. Irinotecan was given intraperitoneally at 40 mg/kg five times every 5 d, and expression profiles were evaluated at d 25 in tumors from treated and untreated animals. Unexpectedly, the in vivo antitumor activity of irinotecan was closely linked to a downregulation of hypoxia-inducible factor-1alpha (HIF1A) target genes along with an inhibition of HIF1A protein accumulation. The consequence was a decrease in tumor angiogenesis leading to tumor size stabilization. These results highlight the molecular basis for the antitumor activity of a widely used anticancer agent, and the method used opens the way for mechanistic studies of the in vivo activity of other anticancer therapies.
Référence
Mol Med. 2012 Feb 10;18(1):83-94