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Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts.

Abstract
We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1alpha protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1alpha protein expression in U251-HRE glioblastoma xenografts. Concomitant with HIF-1alpha inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissue. These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients.
AuthorsAnnamaria Rapisarda, Jessica Zalek, Melinda Hollingshead, Till Braunschweig, Badarch Uranchimeg, Carrie A Bonomi, Suzanne D Borgel, John P Carter, Stephen M Hewitt, Robert H Shoemaker, Giovanni Melillo
JournalCancer research (Cancer Res) Vol. 64 Issue 19 Pg. 6845-8 (Oct 01 2004) ISSN: 0008-5472 [Print] United States
PMID15466170 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Topoisomerase I Inhibitors
  • Transcription Factors
  • Topotecan
  • Luciferases
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage)
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Drug Administration Schedule
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Glioblastoma (blood supply, drug therapy, metabolism, pathology)
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luciferases (antagonists & inhibitors, biosynthesis, genetics)
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic (drug therapy, metabolism)
  • Topoisomerase I Inhibitors
  • Topotecan (administration & dosage)
  • Transcription Factors (antagonists & inhibitors, biosynthesis, genetics)
  • Xenograft Model Antitumor Assays

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