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

Ross J. Maxwell, John Wilson, Vivien E. Prise, Borivoj Vojnovic, Gordon J. Rustin, Martin A. Lodge, Gillian M. Tozer

Research output: Contribution to journalArticle

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, Ktrans, which is related to blood flow rate and permeability of the tumour vasculature to Gd-DTPA, was calculated from the uptake data. Ktrans 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 Ktrans was smaller than that in tumour blood flow, the time course and dose-dependency patterns were very similar. The apparent extravascular extracellular volume fraction, νe, 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 Ktrans 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.

Original languageEnglish (US)
Pages (from-to)89-98
Number of pages10
JournalNMR in biomedicine
Volume15
Issue number2
DOIs
StatePublished - Mar 21 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

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