In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1α target genes and decreases tumor angiogenesis

Mol Med. 2012 Feb 10;18(1):83-94. doi: 10.2119/molmed.2011.00120.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • DNA Topoisomerases, Type I / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Irinotecan
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Topoisomerase I Inhibitors / therapeutic use*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Topoisomerase I Inhibitors
  • Irinotecan
  • DNA Topoisomerases, Type I
  • Camptothecin