Evaluation of the anti-vascular effects of combretastatin in rodent tumours by dynamic contrast enhanced MRI.

Abstract

The anti-vascular effects of the tubulin binding agent, disodium combretastatin A-4 3-O-phosphate (CA-4-P), have been investigated in the rat P22 carcinosarcoma by measurements of radiolabelled iodoantipyrine uptake and dynamic contrast-enhanced MRI. The iodoantipyrine estimates of absolute tumour blood flow showed a reduction from 0.35 to 0.04 ml g(-1) min(-1) 6 h after 10 mg kg(-1) CA-4-P and to <0.01 ml g(-1) min(-1) after 100 mg kg(-1). Tumour blood flow recovered to control values 24 h after 10 mg kg(-1) CA-4-P, but there was no recovery by 24 h after the higher dose. Dynamic contrast-enhanced MR images were obtained at 4.7 T, following injection of 0.1 mmol kg(-1) Gd-DTPA and analysed assuming a model arterial input function. A parameter, K(trans), which is related to blood flow rate and permeability of the tumour vasculature to Gd-DTPA, was calculated from the uptake data. K(trans) showed a reduction from 0.34 to 0.11 min(-1) 6 h after 10 mg kg(-1) CA-4-P and to 0.07 min(-1) after 100 mg kg(-1). Although the magnitude of changes in K(trans) was smaller than that in tumour blood flow, the time course and dose-dependency patterns were very similar. The apparent extravascular extracellular volume fraction, nu(e), showed a four-fold reduction 6 h after 100 mg kg(-1) CA-4-P, possibly associated with vascular shutdown within large regions of the tumour. These results suggest that K(trans) values for Gd-DTPA uptake into tumours could be a useful non-invasive indicator of blood flow changes induced by anti-vascular agents such as combretastatin.

• Authors: Ross J Maxwell, John Wilson, Vivien E Prise, Borivoj Vojnovic, Gordon J Rustin, Martin A Lodge, Gillian M Tozer
• Journal: NMR in biomedicine (NMR Biomed) Vol. 15 Issue 2 Pg. 89-98 (Apr 2002) ISSN: 0952-3480 [Print] England
• PMID: 11870904 (Publication Type: Journal Article)
• Copyright: Copyright 2002 John Wiley & Sons, Ltd.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Phytogenic
• Bibenzyls
• Contrast Media
• Iodine Radioisotopes
• Stilbenes
• combretastatin
• Gadolinium DTPA
• Antipyrine
• iodoantipyrine

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Antipyrine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Bibenzyls (therapeutic use)
• Carcinosarcoma (blood supply, diagnostic imaging, drug therapy, pathology)
• Contrast Media
• Gadolinium DTPA
• Iodine Radioisotopes (pharmacokinetics, therapeutic use)
• Magnetic Resonance Imaging (methods)
• Male
• Radionuclide Imaging
• Rats
• Stilbenes