Vessel size index magnetic resonance imaging to monitor the effect of antivascular treatment in a rodent tumor model.
OBJECTIVE
Vascular disrupting agents are anticancer agents that typically produce a cytostatic tumor response. Vessel size index magnetic resonance imaging (MRI) allows for the estimation of the fractional blood volume (fBV) and blood vessel size (Rv). We assessed whether the vessel size index parameters provided imaging biomarkers for detecting early tumor response to a vascular disrupting agent.


METHODS
GH3 prolactinomas were grown subcutaneously in 12 rats. Vessel size index MRI was performed with Sinerem, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, to determine the tumor fBV and Rv. MRI was performed before and at 24 h after treatment with either the vascular disrupting agent, 5,6-dimethylxanthenone 4-acetic acid (DMXAA) (n = 6) or with the drug vehicle (n = 6). After treatment, the tumors were analyzed histologically and correlates with the MRI findings sought.


RESULTS
Histogram analysis showed non-normal distributions of Rv and fBV. The 25th percentiles of the fBV and Rv were significantly reduced (p < 0.01) after treatment with DMXAA, with an increase in the regions of low-measured fBV. For the treated and control tumors, the fraction of tumor with an fBV of < or =1% correlated with the histologically determined percentage of necrosis (r = 0.77, p < 0.005). The fraction of tumor with an fBV of < or =1% in treated tumors was significantly increased compared with before treatment (p < 0.05) and with that in the controls (p < 0.05).


CONCLUSIONS
The vessel size index results were consistent with the known action of DMXAA to cause vascular collapse, with histogram analysis of the fBV providing the most sensitive indicator of response. In particular, the parameter, the fraction of tumor with an fBV of < or =1% is a potential biomarker that correlates with the histopathologic measure of tumor necrosis.
Division of Cardiac and Vascular Sciences, St. George's, University of London, Cranmer Terrace, London, United Kingdom. f.howe@sgul.ac.uk
Franklyn A
FA
Howe
Lesley D
LD
McPhail
John R
JR
Griffiths
Dominick J O
DJ
McIntyre
Simon P
SP
Robinson
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001810:Blood Volume; D001811:Blood Volume Determination / Q000379:methods*; D003287:Contrast Media; D003911:Dextrans; D005260:Female; D052203:Ferrosoferric Oxide; D007501:Iron; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D009929:Organ Size; D010087:Oxides; D015175:Prolactinoma / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011920:Rats, Inbred WF; D012039:Regional Blood Flow; D044004:Xanthones / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; D044004:Xanthones; C097921:ferumoxtran-10; C066668:vadimezan; D007501:Iron; D052203:Ferrosoferric Oxide