title: Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha.
abstract: The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that PX-478 given to mice suppresses HIF-1alpha levels in HT-29 human colon cancer xenografts and inhibits the expression of HIF-1 target genes including vascular endothelial growth factor and the glucose transporter-1. PX-478 shows antitumor activity against established (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77 small cell lung cancer and log cell kills up to 3.0 for other tumors including HT-29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1 pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed 64% regression, which was greater than for smaller tumors. The antitumor response to PX-478 was positively correlated with tumor HIF-1alpha levels (P < 0.02) and was accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of HIF-1alpha and HIF-1 transcription factor activity in human tumor xenografts and has marked antitumor activity against even large tumor xenografts, which correlates positively with HIF-1alpha levels.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Welsh
authors.forename: Ryan
authors.initials: R
authors.lastname: Williams
authors.forename: Lynn
authors.initials: L
authors.lastname: Kirkpatrick
authors.forename: Gillian
authors.initials: G
authors.lastname: Paine-Murrieta
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000097:blood; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009150:Mustard Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D010666:Phenylpropionates / Q000737:chemistry / Q000493:pharmacokinetics*; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009150:Mustard Compounds; D010666:Phenylpropionates; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin