Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1α using PX-478

Bénédicte F. Jordan, Matthew Runquist, Natarajan Raghunand, Amanda Baker, Ryan Williams, Lynn Kirkpatrick, Garth Powis, Robert J. Gillies

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1α, 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 pre-clinical findings, both of these imaging endpoints will be included in the clinical trial of PX-478.

Original languageEnglish (US)
Pages (from-to)475-485
Number of pages11
JournalNeoplasia
Volume7
Issue number5
DOIs
StatePublished - May 2005

Keywords

  • Diffusion Magnetic Resonance Imaging
  • Dynamic Contrast-Enhanced Magnetic Resonance Imaging
  • HT-29 tumors
  • Molecular imaging
  • PX-478

ASJC Scopus subject areas

  • Cancer Research

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