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.
The authors wish to acknowledge the biocomputing, bioinformatics and microarray facilities at the Institut de Génétique et de Biologie Moléculaire et Cellulaire. They also gratefully acknowledge Christiane Arnold, Mathilde Arrivé, Nathalie Hamelin and Laetitia Ruck for excellent technical assistance.
This work was supported by the Ligue Régionale contre le Cancer (Haut-Rhin, Bas-Rhin), the Institut National du Cancer (CETIRICOL, PL06.008), the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Université de Strasbourg and the Hôpitaux Universitaires de Strasbourg.
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