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- Title
In Vivo Topoisomerase I Inhibition Attenuates the Expression of Hypoxia-Inducible Factor 1α Target Genes and Decreases Tumor Angiogenesis.
- Authors
Guérin, Eric; Raffelsberger, Wolfgang; Pencreach, Erwan; Maier, Armin; Neuville, Agnès; Schneider, Anne; Bachellier, Philippe; Rohr, Serge; Petitprez, Amélie; Poch, Olivier; Moras, Dino; Oudet, Pierre; Larsen, Annette K.; Gaub, Marie-Pierre; Guenot, Dominique
- Abstract
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 patientderived 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.
- Subjects
DNA topoisomerase I; IRINOTECAN; HYPOXEMIA; TUMORS; ANTINEOPLASTIC agents; NEOVASCULARIZATION inhibitors
- Publication
Molecular Medicine, 2012, Vol 18, Issue 1, p83
- ISSN
1076-1551
- Publication type
Article
- DOI
10.2119/molmed.2011.00120