title: Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging.
abstract: ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time-concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T(2)*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R(2)* (=1/T(2)*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.
authors.affiliation: Cancer Research UK Biomedical Magnetic Resonance Research Group, St George's Hospital Medical School, London SW17 ORE, UK. s.robinson@sghms.ac.uk
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.forename: D J O
authors.initials: DJ
authors.lastname: McIntyre
authors.forename: D
authors.initials: D
authors.lastname: Checkley
authors.forename: J J
authors.initials: JJ
authors.lastname: Tessier
authors.forename: F A
authors.initials: FA
authors.lastname: Howe
authors.forename: J R
authors.initials: JR
authors.lastname: Griffiths
authors.forename: S E
authors.initials: SE
authors.lastname: Ashton
authors.forename: A J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: D C
authors.initials: DC
authors.lastname: Blakey
authors.forename: J C
authors.initials: JC
authors.lastname: Waterton
mesh_terms: D000818:Animals; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000098:blood supply* / Q000473:pathology / Q000662:veterinary; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009336:Necrosis; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000662:veterinary; D015175:Prolactinoma / Q000098:blood supply* / Q000473:pathology / Q000662:veterinary; D051381:Rats; D012039:Regional Blood Flow
chemical_list: D014408:Biomarkers, Tumor; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds