Differential sensitivity of two adenocarcinoma xenografts to the anti‐vascular drugs combretastatin A4 phosphate and 5,6‐dimethylxanthenone‐4‐acetic acid, assessed using MRI and MRS

Beauregard, Daniel A.; Pedley, RB; Hill, Sally A.; Brindle, Kevin M.

doi:10.1002/nbm.723

Cited by 59 publications

(43 citation statements)

References 14 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Evelhoch

LoRusso

et al. 2004

Clinical Cancer Research

157

103

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Purpose: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors.Experimental Design: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space.Results: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6 -48% at 50 mg/kg (n ‫؍‬ 3)], 58 -91% at 100 mg/kg (n ‫؍‬ 4), and 11-93% at 200 mg/kg (n ‫؍‬ 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n ‫؍‬ 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P ‫؍‬ 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m 2 and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36 -72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter-and intratumor coefficients of variation were 64 and 18%.Conclusions: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.

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Section: Discussionmentioning

confidence: 99%

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

Evelhoch

LoRusso

et al. 2004

Clinical Cancer Research

157

103

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“…We recently showed acute hypoxiation within 90 mins following CA4P administration to rats bearing syngeneic breast 13762NF tumors using MRI (30). Rapid vascular shut-down in tumors after administration of CA4P to animals and patients has also been observed by many other imaging modalities including positron emission tomography (PET) based on the distribution of 15 O water (31), DCE MRI (24,32,33), DCE computed tomography (CT) (34), 19 F MRI of tumor oxygenation (30), Laser Doppler flowmetry (35), radiolabeled iodoantipyrine (IAP) uptake (27), near infrared spectroscopy (36), interstitial fluid pressure (IFP) (35) and intra vital microscopy (37). By comparison bioluminescence imaging is particularly inexpensive and easy to apply in animal models and we believe it could be an effective screening tool for evaluation and comparison of vascular targeting agents as well as long-term tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Bioluminescent imaging (BLI) has found significant use in evaluating long-term cancer therapy in small animals. We have now tested the feasibility of using BLI to assess acute effects of the vascular disrupting agent Combretastatin A4 phosphate (CA4P) on luciferase expressing MDA-MB-231 human breast tumor cells growing as xenografts in mice. Following administration of luciferin substrate, there is a rapid increase in light emission reaching a maximum after about six minutes, which gradually decreases over the following 20 min. The kinetics of light emission are highly reproducible, however, following IP administration of CA4P (120 mg/kg), the detected light emission was decreased between 50 and 90 percent and time to maximum was significantly delayed. Twenty-four hours later, there was some recovery of light emission following further administration of luciferin substrate. Comparison with dynamic contrast-enhanced MRI based on the paramagnetic contrast agent Omniscan showed comparable changes in the tumors consistent with the previous literature. Histology also confirmed shutdown of tumor vascular perfusion. We believe this provides an important novel application for BLI, which could have widespread application in screening novel therapeutics expected to cause acute vascular changes in tumors.

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“…Magnetic resonance imaging (MRI) is one approach that affords such biomarkers of response to antivascular therapies, and drug efficacy has been demonstrated in both preclinical (Beauregard et al, 2002;Maxwell et al, 2002) and clinical studies (Dowlati et al, 2002;Galbraith et al, 2002). In this study, we describe the use of two MRI techniques for the noninvasive assessment of the dose-dependent antivascular activity of ZD6126 on tumour perfusion.…”

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confidence: 99%

Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging

et al. 2003

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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.

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Differential sensitivity of two adenocarcinoma xenografts to the anti‐vascular drugs combretastatin A4 phosphate and 5,6‐dimethylxanthenone‐4‐acetic acid, assessed using MRI and MRS

Cited by 59 publications

References 14 publications

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

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

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

Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging

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