Evaluation of the anti-vascular effects of combretastatin in rodent tumours by dynamic contrast enhanced MRI.
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.
Maxwell
Ross J
RJ
Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK. maxwell@gci.ac.uk
Wilson
John
J
Prise
Vivien E
VE
Vojnovic
Borivoj
B
Rustin
Gordon J
GJ
Lodge
Martin A
MA
Tozer
Gillian M
GM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001632:Bibenzyls / Q000627:therapeutic use*; D002296:Carcinosarcoma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media; D019786:Gadolinium DTPA; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D011877:Radionuclide Imaging; D051381:Rats; D013267:Stilbenes
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D003287:Contrast Media; D007457:Iodine Radioisotopes; D013267:Stilbenes; C040105:combretastatin; D019786:Gadolinium DTPA; D000983:Antipyrine; C008135:iodoantipyrine