Journal
NEOPLASIA
Volume 7, Issue 5, Pages 475-485Publisher
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.04628
Keywords
PX-478; HT-29 tumors; dynamic contrast-enhanced magnetic resonance imaging; diffusion magnetic resonance imaging; molecular imaging
Categories
Funding
- NCI NIH HHS [CA98920, R01 CA077575, R24 CA083148, CA077575, P30 CA03074, U54 CA090821, R01 CA098920, U54 CA90821] Funding Source: Medline
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PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1 alpha, 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.
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