In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1α target genes and decreases tumor angiogenesis.
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-1α (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.
EA 4438 Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
Eric
E
Guérin
Wolfgang
W
Raffelsberger
Erwan
E
Pencreach
Armin
A
Maier
Agnès
A
Neuville
Anne
A
Schneider
Philippe
P
Bachellier
Serge
S
Rohr
Amélie
A
Petitprez
Olivier
O
Poch
Dino
D
Moras
Pierre
P
Oudet
Annette K
AK
Larsen
Marie-Pierre
MP
Gaub
Dominique
D
Guenot
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin