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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Cell Division / drug effects
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Cell Line, Tumor
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Drug Administration Schedule
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Enzyme Inhibitors / pharmacology
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Female
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Glioblastoma / blood supply
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Luciferases / antagonists & inhibitors
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Luciferases / biosynthesis
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Luciferases / genetics
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Mice
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Mice, Nude
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / metabolism
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Topoisomerase I Inhibitors
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Topotecan / administration & dosage*
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Topoisomerase I Inhibitors
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Transcription Factors
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Topotecan
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Luciferases