1: Neoplasia. 2005 May;7(5):475-85. 

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

Jordan BF, Runquist M, Raghunand N, Baker A, Williams R, Kirkpatrick L, Powis G,
Gillies RJ.

Department of Biochemistry, University of Arizona Health Sciences Center,
Tucson, AZ 85724, USA.

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.

PMID: 15967100 [PubMed - in process]