Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours

ObjectivesTo evaluate effects of a vascular-disrupting agent on rodent tumour models.MethodsTwenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [18F]fluorodeoxyglucose micro-positron emission tomography (18F-FDG µPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUVmax) from FDG µPET were quantified and correlated with postmortem microangiography and histopathology.ResultsIn the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUVmax dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05).ConclusionsThe imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.

[1]  S. Larson,et al.  The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development , 2005, Clinical Cancer Research.

[2]  D. Collins,et al.  Diffusion-weighted MRI in the body: applications and challenges in oncology. , 2007, AJR. American journal of roentgenology.

[3]  A R Padhani,et al.  Diffusion-weighted MRI: a new functional clinical technique for tumour imaging. , 2006, The British journal of radiology.

[4]  Y. Ni,et al.  Diffusion-weighted MR imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats. , 2005, Radiology.

[5]  K. Jain,et al.  Cancer biomarkers: current issues and future directions. , 2007, Current opinion in molecular therapeutics.

[6]  J. Nuyts,et al.  Effect of corticosteroids on 18F-FDG uptake in tumor lesions after chemotherapy. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[7]  James H Thrall,et al.  Biomarkers in imaging: realizing radiology's future. , 2003, Radiology.

[8]  B Vojnovic,et al.  Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. , 1999, Cancer research.

[9]  Q. Pang,et al.  The effect of combretastatin A4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on water diffusion and blood perfusion in tumours , 2008, Acta oncologica.

[10]  P. Choyke,et al.  Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. , 2009, Neoplasia.

[11]  D. Collins,et al.  Dynamic magnetic resonance imaging of tumor perfusion , 2004, IEEE Engineering in Medicine and Biology Magazine.

[12]  R. Hustinx,et al.  Within-patient variability of (18)F-FDG: standardized uptake values in normal tissues. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[13]  M. Knopp,et al.  Estimating kinetic parameters from dynamic contrast‐enhanced t1‐weighted MRI of a diffusable tracer: Standardized quantities and symbols , 1999, Journal of magnetic resonance imaging : JMRI.

[14]  W. Colburn,et al.  Biomarkers in Drug Discovery and Development: From Target Identification through Drug Marketing , 2003, Journal of clinical pharmacology.

[15]  Joanna Leadbetter,et al.  Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126 , 2004, Clinical Cancer Research.

[16]  G. Barendsen,et al.  Cellular proliferation patterns in an experimental rhabdomyosarcoma in the rat. , 1967, European journal of cancer.

[17]  M. Wendland,et al.  Osteogenic sarcoma: noninvasive in vivo assessment of tumor necrosis with diffusion-weighted MR imaging. , 1998, Radiology.

[18]  Hilde Bosmans,et al.  Liver tumor model with implanted rhabdomyosarcoma in rats: MR imaging, microangiography, and histopathologic analysis. , 2006, Radiology.

[19]  N. Avril,et al.  Functional PET imaging in cancer drug development. , 2007, Future oncology.

[20]  P. S. Tofts,et al.  Rapid Measurement of Capillary Permeability Using the Early Part of the Dynamic Gd-DTPA MRI Enhancement Curve , 1993 .

[21]  F. Howe,et al.  Single dose of the antivascular agent, ZD6126 (N-acetylcolchinol-O-phosphate), reduces perfusion for at least 96 hours in the GH3 prolactinoma rat tumor model. , 2004, Neoplasia.

[22]  J. Eng,et al.  Sample Size Estimation : How Many Individuals Should Be Studied ? , 2022 .

[23]  T. Paunesku,et al.  In Vivo Diffusion-Weighted Imaging of Liver Tumor Necrosis in the VX2 Rabbit Model at 1.5 Tesla , 2006, Investigative radiology.

[24]  D. Le Bihan,et al.  Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. , 1988, Radiology.

[25]  E. Voest,et al.  Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Hilde Bosmans,et al.  Treatment of Rodent Liver Tumor With Combretastatin A4 Phosphate: Noninvasive Therapeutic Evaluation Using Multiparametric Magnetic Resonance Imaging in Correlation With Microangiography and Histology , 2008, Investigative radiology.

[27]  M. Horsman,et al.  Vascular targeting effects of ZD6126 in a C3H mouse mammary carcinoma and the enhancement of radiation response. , 2003, International journal of radiation oncology, biology, physics.

[28]  R K Jain,et al.  Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. , 1990, Cancer research.

[29]  Y. Ni,et al.  Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging. , 2005, Radiology.

[30]  H. Augustin,et al.  Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. , 2000, Cancer research.

[31]  H. Malcolm Hudson,et al.  Accelerated image reconstruction using ordered subsets of projection data , 1994, IEEE Trans. Medical Imaging.

[32]  D. Blakey,et al.  ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature. , 2002, Cancer research.

[33]  P. Tofts.  Modeling tracer kinetics in dynamic Gd‐DTPA MR imaging , 1997, Journal of magnetic resonance imaging : JMRI.

[34]  L. Feldkamp,et al.  Practical cone-beam algorithm , 1984 .

[35]  L. Shen,et al.  Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. , 2008, Radiology.

[36]  F. Westwood,et al.  Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  David J Collins,et al.  Dynamic magnetic resonance imaging of tumor perfusion. Approaches and biomedical challenges. , 2004, IEEE engineering in medicine and biology magazine : the quarterly magazine of the Engineering in Medicine & Biology Society.

[38]  M Van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. , 2000, Journal of the National Cancer Institute.

[39]  J. Waterton,et al.  Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats. , 2007, Neoplasia.

[40]  S. Jaffer,et al.  Beyond Hematoxylin and Eosin—The Role of Immunohistochemistry in Surgical Pathology , 2004, Cancer investigation.

[41]  Barjor Gimi,et al.  Diffusion-weighted and macromolecular contrast enhanced MRI of tumor response to antivascular therapy with ZD6126 , 2007, Cancer biology & therapy.

[42]  A. Ryan,et al.  Vascular targeting in pancreatic cancer: the novel tubulin-binding agent ZD6126 reveals antitumor activity in primary and metastatic tumor models. , 2005, Neoplasia.

[43]  J R Griffiths,et al.  Clinical studies. , 2005, Advances in pharmacology.

[44]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[45]  R. Kerbel,et al.  Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development , 2004, Clinical Cancer Research.

[46]  R. Lenkinski,et al.  Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model? , 2009, Radiology.

[47]  A. Gotlieb.  The endothelial cytoskeleton: organization in normal and regenerating endothelium. , 1990, Toxicologic pathology.

[48]  J. Griffiths,et al.  The response of RIF-1 fibrosarcomas to the vascular-disrupting agent ZD6126 assessed by in vivo and ex vivo 1H magnetic resonance spectroscopy. , 2006, Neoplasia.