Susceptibility contrast magnetic resonance imaging determination of fractional tumor blood volume: a noninvasive imaging biomarker of response to the vascular disrupting agent ZD6126.
OBJECTIVE
To assess tumor fractional blood volume (xi), determined in vivo by susceptibility contrast magnetic resonance imaging (MRI) as a noninvasive imaging biomarker of tumor response to the vascular disrupting agent ZD6126.


METHODS
The transverse MRI relaxation rate R(2)( *) of rat GH3 prolactinomas was quantified prior to and following injection of 2.5 mgFe/kg feruglose, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, and xi (%) was determined from the change in R(2)( *). The rats were then treated with either saline or 50 mg/kg ZD6126, and xi measured again 24 hours later. Following posttreatment MRI, Hoechst 33342 (15 mg/kg) was administered to the rats and histological correlates from composite images of tumor perfusion and necrosis sought.


RESULTS
Irrespective of treatment, tumor volume significantly increased over 24 hours. Saline-treated tumors showed no statistically significant change in xi, whereas a significant (p = 0.002) 70% reduction in xi of the ZD6126-treated cohort was determined. Hoechst 33342 uptake was associated with viable tumor tissue and was significantly (p = 0.004) reduced and restricted to the rim of the ZD6126-treated tumors. A significant positive correlation between posttreatment xi and Hoechst 33342 uptake was obtained (r = 0.83, p = 0.002), providing validation of the MRI-derived measurements of fractional tumor blood volume.


CONCLUSIONS
These data clearly highlight the potential of susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide contrast agents to provide quantitative imaging biomarkers of fractional tumor blood volume at high spatial resolution to assess tumor vascular status and response to vascular disrupting agents.
Robinson
Simon P
SP
Department of Basic Medical Sciences, St. George's, University of London, London, United Kingdom. Simon.Robinson@icr.ac.uk
Howe
Franklyn A
FA
Griffiths
John R
JR
Ryan
Anderson J
AJ
Waterton
John C
JC
D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics; D001810:Blood Volume / Q000187:drug effects* / Q000502:physiology; D003287:Contrast Media; D003911:Dextrans; D005260:Female; D052203:Ferrosoferric Oxide; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D007501:Iron; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010087:Oxides; D010911:Pituitary Neoplasms; D015175:Prolactinoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats
D001562:Benzimidazoles; D003287:Contrast Media; D003911:Dextrans; D005456:Fluorescent Dyes; D058185:Magnetite Nanoparticles; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D010087:Oxides; C097921:ferumoxtran-10; D007501:Iron; C017807:bisbenzimide ethoxide trihydrochloride; D052203:Ferrosoferric Oxide