Rat tumor response to the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid as measured by dynamic contrast-enhanced magnetic resonance imaging, plasma 5-hydroxyindoleacetic acid levels, and tumor necrosis.
The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using K(trans) and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers. High-performance liquid chromatography (HPLC) was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor K(trans) and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in K(trans) or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.
McPhail
Lesley D
LD
Division of Basic Medical Sciences, St. George's, University of London, London, UK. lesley@sgul.ac.uk
McIntyre
Dominick J O
DJ
Ludwig
Christian
C
Kestell
Philip
P
Griffiths
John R
JR
Kelland
Lloyd R
LR
Robinson
Simon P
SP
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers; D002199:Capillary Permeability; D045744:Cell Line, Tumor / Q000637:transplantation; D003287:Contrast Media; D004305:Dose-Response Relationship, Drug; D005260:Female; D019786:Gadolinium DTPA; D007211:Indoles / Q000097:blood*; D008279:Magnetic Resonance Imaging; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010911:Pituitary Neoplasms / Q000473:pathology*; D015175:Prolactinoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D011920:Rats, Inbred WF; D040521:Subcutaneous Tissue; D044004:Xanthones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D003287:Contrast Media; D007211:Indoles; D044004:Xanthones; C066668:vadimezan; C026785:5-hydroxyindole; C064925:gadodiamide; D019786:Gadolinium DTPA