Non-invasive imaging of combretastatin activity in two tumor models: Association with invasive estimates.
BACKGROUND
The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P.


METHODS
Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).


RESULTS
Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment.


CONCLUSIONS
Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.
Nielsen
Thomas
T
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. thomas@oncology.dk
Murata
Rumi
R
Maxwell
Ross J
RJ
Stødkilde-Jørgensen
Hans
H
Ostergaard
Leif
L
Ley
Carsten D
CD
Kristjansen
Paul E G
PE
Horsman
Michael R
MR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003287:Contrast Media; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods; D008325:Mammary Neoplasms, Experimental / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism; D012509:Sarcoma / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D013223:Statistics as Topic; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D013267:Stilbenes; D009569:Nitric Oxide; C058728:fosbretabulin