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 Ã 2 , which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R Ã 2 (¼ 1=T Ã 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.

Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126

“…The dose-dependent changes measured in the murine and human tumors are consistent with the results of a study of ZD6126 in a rat prolactinoma model (25) and the preliminary findings from a Phase I trial for CA4P (23). In contrast, there was no evidence of a dose response reduction in tumor IAUC after the administration of DMXAA to patients (24).…”

“…The results reported here show the potential of using DCE-MRI in ZD6126 dose-finding studies in humans. Although a number of studies have already shown the potential of using DCE-MRI with the vascular-targeting agents CA4P (7,(13)(14)(15)(21)(22)(23) and DMXAA (22,24), there is only one published study for ZD6126 (25). In addition, we have shown that ZD6126 dosedependent changes can be measured using MRI and that the approach developed in murine tumors can be translated into the clinic.…”

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

“…DCE-MRI measurements showed that after just 2 days patupilone significantly decreased the rBVol (P = 0.0005). Other vascular variables, such as vessel permeability and overall perfusion, were unaffected, a distinct difference in vascular response in comparison with therapies that target vascular endothelial growth factor (24,37) or the vascular endothelial growth factor receptor (33) or the endothelial cells directly (38,39) and not necessarily expected given that other antivascular/disruptive therapies can decrease permeability and/or perfusion (9,40). Vascular casts of tumors made 2 days after treatment showed a trend for patupilone to induce a decrease in blood vessel mass, and at this time point, the tumor IFP was also decreased (P = 0.02).…”

Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

“…DCE MRI was included as part of the Phase I clinical trials of CA4P (24,25). Results of preclinical and clinical DCE MRI studies have shown a reversible change in vascular perfusion in the tumor periphery following a single dose of VTA (26)(27)(28)(29).…”