Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts.
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.
Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. melillog@ncifcrd.gov
Annamaria
A
Rapisarda
Jessica
J
Zalek
Melinda
M
Hollingshead
Till
T
Braunschweig
Badarch
B
Uranchimeg
Carrie A
CA
Bonomi
Suzanne D
SD
Borgel
John P
JP
Carter
Stephen M
SM
Hewitt
Robert H
RH
Shoemaker
Giovanni
G
Melillo
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; D019772:Topotecan; D008156:Luciferases