Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.
OBJECTIVE
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle.


METHODS
Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study.


RESULTS
Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose.


CONCLUSIONS
DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.
Galbraith
Susan M
SM
Department of Medical Oncology and Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Rustin
Gordon J S
GJ
Lodge
Martin A
MA
Taylor
N Jane
NJ
Stirling
J James
JJ
Jameson
Michael
M
Thompson
Paul
P
Hough
David
D
Gumbrell
Lindsey
L
Padhani
Anwar R
AR
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003287:Contrast Media / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007089:Image Enhancement; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008833:Microcirculation / Q000187:drug effects* / Q000473:pathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000033:anatomy & histology*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D015203:Reproducibility of Results; D014966:Xanthenes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044004:Xanthones
D000970:Antineoplastic Agents; D003287:Contrast Media; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan