MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model

Abstract. The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (~30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (KPS) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (KPS) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and KPS values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (KPS), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy.

[1]  C. Sotak,et al.  Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP-DO3A) in the nephrectomized rat. , 1992, Magnetic resonance imaging.

[2]  J. Mestan,et al.  PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. , 2000, Cancer research.

[3]  C. Angeletti,et al.  Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. , 1997, Journal of the National Cancer Institute.

[4]  T. Helbich,et al.  Prostate cancer tumor grade differentiation with dynamic contrast-enhanced MR imaging in the rat: comparison of macromolecular and small-molecular contrast media--preliminary experience. , 1999, Radiology.

[5]  D M Shames,et al.  Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media. , 1998, AJR. American journal of roentgenology.

[6]  C. Higgins,et al.  Three‐dimensional MR imaging of pulmonary vessels and parenchyma with NC100150 injection (Clariscan™) , 2000, Journal of magnetic resonance imaging : JMRI.

[7]  M. Itoman,et al.  Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. , 2002, Biochemical and biophysical research communications.

[8]  M. Ogan,et al.  Albumin labeled with Gd-DTPA: an intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization. , 1987, Investigative radiology.

[9]  Martin R. Schneider,et al.  PTK 787 / ZK 222584 , a Novel and Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases , Impairs Vascular Endothelial Growth Factor-induced Responses and Tumor Growth after Oral Administration , 2000 .

[10]  L. Ellis,et al.  Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. , 2000, Anti-cancer drug design.

[11]  J. Fargnoli,et al.  Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. , 2001, Cancer research.

[12]  R M Weisskoff,et al.  Water diffusion and exchange as they influence contrast enhancement , 1997, Journal of magnetic resonance imaging : JMRI.

[13]  C. Bucana,et al.  Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  M. Moseley,et al.  Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha. , 1990, Cancer research.

[15]  G. Palade,et al.  Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. , 1995, Journal of cell science.

[16]  T. N. Campbell,et al.  Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  C. Higgins,et al.  Histologic confirmation of microvascular hyperpermeability to macromolecular MR contrast medium in reperfused myocardial infarction , 1998, Journal of magnetic resonance imaging : JMRI.

[18]  T. Veikkola,et al.  Regulation of angiogenesis via vascular endothelial growth factor receptors. , 2000, Cancer research.

[19]  D. Cheresh,et al.  Integrins and cancer. , 1996, Current opinion in cell biology.

[20]  L. Ellis,et al.  Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. , 1995, Cancer research.

[21]  R. Weissleder,et al.  Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. , 1990, Radiology.

[22]  M. Moseley,et al.  Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha. , 1990, Cancer research.

[23]  K. Hoekman SU6668, a multitargeted angiogenesis inhibitor. , 2001, Cancer journal.

[24]  R. Brasch,et al.  AUR Memorial Award 1991. Immunogenicity of gadolinium-based contrast agents for magnetic resonance imaging. Induction and characterization of antibodies in animals. , 1991, Investigative radiology.

[25]  R. Brasch,et al.  Contrast-enhanced MR imaging assessment of tumor capillary permeability: effect of irradiation on delivery of chemotherapy. , 1996, Radiology.

[26]  D M Shames,et al.  MR imaging characterization of microvessels in experimental breast tumors by using a particulate contrast agent with histopathologic correlation. , 2001, Radiology.

[27]  D M Shames,et al.  Measurement of capillary permeability to macromolecules by dynamic magnetic resonance imaging: A quantitative noninvasive technique , 1993, Magnetic resonance in medicine.

[28]  J. Cherrington,et al.  New paradigms for the treatment of cancer: the role of anti-angiogenesis agents. , 2000, Advances in cancer research.

[29]  R. Brasch,et al.  Differentiation of alveolitis and pulmonary fibrosis with a macromolecular MR imaging contrast agent. , 1992, Radiology.

[30]  A. Ullrich,et al.  Flk-1 as a target for tumor growth inhibition. , 1996, Cancer research.

[31]  B R Rosen,et al.  Improving MR quantification of regional blood volume with intravascular T1 contrast agents: Accuracy, precision, and water exchange , 1996, Magnetic resonance in medicine.

[32]  I. Fidler,et al.  Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. , 2000, Cancer research.

[33]  Emmanuelle Canet,et al.  Contrast‐enhanced 3D‐TOF MRA of peripheral vessels: Intravascular versus extracellular MR contrast media , 1998, Journal of magnetic resonance imaging : JMRI.

[34]  R. Brasch,et al.  Safety aspects and pharmacokinetics of inhaled aerosolized gadolinium , 1993, Journal of magnetic resonance imaging : JMRI.

[35]  T. Roberts,et al.  Physiologic measurements by contrast‐enhanced MR imaging: Expectations and limitations , 1997, Journal of magnetic resonance imaging : JMRI.

[36]  R. Brasch,et al.  Quantification of liver blood volume: comparison of ultra short ti inversion recovery echo planar imaging (ulstir‐epi), with dynamic 3d‐gradient recalled echo imaging , 1995, Magnetic resonance in medicine.

[37]  N. van Bruggen,et al.  Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. , 1998, Cancer investigation.

[38]  E Biganzoli,et al.  Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  C. Brock,et al.  Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer , 2002, European Respiratory Journal.

[40]  M. Moseley,et al.  Contrast-enhanced MRI of tumors. Comparison of Gd-DTPA and a macromolecular agent. , 1989, Investigative radiology.