PMID- 15026543
OWN - NLM
STAT- MEDLINE
DCOM- 20041109
LR  - 20220225
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 3
IP  - 3
DP  - 2004 Mar
TI  - Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of 
      hypoxia-inducible factor-1alpha.
PG  - 233-44
AB  - 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.
FAU - Welsh, Sarah
AU  - Welsh S
AD  - Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
FAU - Williams, Ryan
AU  - Williams R
FAU - Kirkpatrick, Lynn
AU  - Kirkpatrick L
FAU - Paine-Murrieta, Gillian
AU  - Paine-Murrieta G
FAU - Powis, Garth
AU  - Powis G
LA  - eng
GR  - CA52995/CA/NCI NIH HHS/United States
GR  - CA90821/CA/NCI NIH HHS/United States
GR  - CA98920/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Mustard Compounds)
RN  - 0 (Phenylpropionates)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 11096-26-7 (Erythropoietin)
SB  - IM
CIN - Mol Cancer Ther. 2004 Mar;3(3):245-6. PMID: 15026544
MH  - Animals
MH  - Antineoplastic Agents/*pharmacokinetics
MH  - Apoptosis
MH  - Area Under Curve
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Erythropoietin/blood
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunohistochemistry
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, SCID
MH  - Monosaccharide Transport Proteins/metabolism
MH  - Mustard Compounds/chemistry/*pharmacokinetics
MH  - Neoplasm Transplantation
MH  - Neoplasms/*drug therapy
MH  - Phenylpropionates/chemistry/*pharmacokinetics
MH  - Time Factors
MH  - Transcription Factors/*antagonists & inhibitors/chemistry
MH  - Vascular Endothelial Growth Factor A/blood/metabolism
EDAT- 2004/03/18 05:00
MHDA- 2004/11/13 09:00
CRDT- 2004/03/18 05:00
PHST- 2004/03/18 05:00 [pubmed]
PHST- 2004/11/13 09:00 [medline]
PHST- 2004/03/18 05:00 [entrez]
PST - ppublish
SO  - Mol Cancer Ther. 2004 Mar;3(3):233-44.