title: Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478.
abstract: PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1alpha, in experimental tumors. The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint(s) is sensitive to this drug's actions. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor hemodynamics and cellularity, respectively. Mice bearing human xenografts were treated either with PX-478 or vehicle, and imaged over time. DW imaging was performed at three b values to generate apparent diffusion coefficient of water (ADCw) maps. For DCE-MRI, a macromolecular contrast reagent, BSA-Gd-DTPA, was used to determine vascular permeability and vascular volume fractions. PX-478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment, which returned to baseline by 48 hours. The anti-VEGF antibody, Avastin, reduced both the permeability and vascular volume. PX-478 had no effect on the perfusion behavior of a drug-resistant tumor system, A-549. Tumor cellularity, estimated from ADCw, was significantly decreased 24 and 36 hours after treatment. This is the earliest significant response of ADC to therapy yet reported. Based on these preclinical findings, both of these imaging endpoints will be included in the clinical trial of PX-478.
authors.affiliation: Department of Biochemistry, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
authors.forename: Matthew
authors.initials: M
authors.lastname: Runquist
authors.forename: Natarajan
authors.initials: N
authors.lastname: Raghunand
authors.forename: Amanda
authors.initials: A
authors.lastname: Baker
authors.forename: Ryan
authors.initials: R
authors.lastname: Williams
authors.forename: Lynn
authors.initials: L
authors.lastname: Kirkpatrick
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000494:pharmacology; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D005260:Female; D006439:Hemodynamics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D009150:Mustard Compounds / Q000494:pharmacology*; D009336:Necrosis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D010539:Permeability; D010666:Phenylpropionates / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003287:Contrast Media; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab