Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment

Anti-angiogenic therapy by blocking VEGF signalling combined with standard chemotherapy is a novel strategy for clinical cancer treatment. The mechanisms for enhanced antitumoral effects are still a matter of controversial debate. Tumor vessel “normalization” upon anti-angiogenic therapy leading to improved drug delivery has been proposed as possible mechanism. Therefore, aim of the study was to investigate tumor microvascular function upon anti-VEGFR treatment in highly vascularized melanomas. A detailed intravital-microscopic analysis of tumor microcirculation including the distribution pattern of vessel diameters and blood flow velocities was performed in melanomas grown in dorsal skinfold chambers of hamsters. Animals with highly vascularized established tumors were treated by a VEGFR tyrosin kinase inhibitor (SU5416) on 3 repetitive days. Tumor tissue oxygenation was measured by phosphorescence quenching technique. Overall tumor microcirculation of subcutaneous tumors was investigated by contrast enhanced MRI (CE-MRI). Vessel density was significantly decreased in treated animals. A significant shift in the distribution patterns towards increased vessel diameters and faster red blood cell velocities in remaining tumor vessels was observed upon anti-VEGF treatment, compensating reduced vascular density. Moreover, a trend towards elevated pO2 levels in treated tumors was observed. Compared to controls, inflow kinetics of tumors quantified by CE-MRI as well as overall uptake of contrast agent in tumor tissue were significantly increased following short-term SU5416 treatment. In conclusion the results confirm temporarily improved tumor microvascular function in highly vascularized melanomas upon short term anti-VEGFR treatment leading to enhanced tumor supply and oxygenation potentially improving the efficacy of simultaneous chemo- or radiotherapy.

[1]  M. Baker,et al.  On-line volume flow rate and velocity profile measurement for blood in microvessels. , 1974, Microvascular research.

[2]  R. Jain,et al.  Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. , 2001, Cancer research.

[3]  K Messmer,et al.  Quantitative analysis of microvascular structure and function in the amelanotic melanoma A-Mel-3. , 1981, Cancer research.

[4]  R Folberg,et al.  Vasculogenic mimicry and tumor angiogenesis. , 2000, The American journal of pathology.

[5]  A. Goetz,et al.  Influence of the shock wave application mode on the growth of A-Mel 3 and SSK2 tumors in vivo. , 1990, Ultrasound in medicine & biology.

[6]  Tracy T Batchelor,et al.  AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. , 2007, Cancer cell.

[7]  S. Baruchel,et al.  Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. , 2000, The Journal of clinical investigation.

[8]  W. Shi,et al.  VEGF-associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy. , 2006, International journal of radiation oncology, biology, physics.

[9]  R Deichmann,et al.  Quantification of T1 values by SNAPSHOT-FLASH NMR imaging , 1992 .

[10]  R. Lucht,et al.  Microcirculation and microvasculature in breast tumors: Pharmacokinetic analysis of dynamic MR image series , 2004, Magnetic resonance in medicine.

[11]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[12]  M. Shibuya,et al.  Anti‐tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model , 2008, Cancer science.

[13]  A G Harris,et al.  Orthogonal polarisation spectral imaging as a new tool for the assessment of antivascular tumour treatment in vivo: a validation study , 2002, British Journal of Cancer.

[14]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[15]  Lei Xu,et al.  Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. , 2004, Cancer cell.

[16]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[17]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[18]  W. Sessa,et al.  Antiangiogenic therapy: creating a unique "window" of opportunity. , 2004, Cancer cell.

[19]  H. Dvorak,et al.  Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. , 1991, Cancer cells.

[20]  N. Andratschke,et al.  Current status of angiogenesis inhibitors combined with radiation therapy. , 2006, Cancer treatment reviews.

[21]  G. Brix,et al.  Paclitaxel encapsulated in cationic lipid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging , 2006, Cancer biology & therapy.

[22]  A. Ullrich,et al.  Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. , 1999, Neoplasia.

[23]  M A Konerding,et al.  Microvascular corrosion casting in the study of tumor vascularity: a review. , 1995, Scanning microscopy.

[24]  K. Jauch,et al.  Angiogenesis in cancer: molecular mechanisms, clinical impact , 2007, Langenbeck's Archives of Surgery.

[25]  Ricky T. Tong,et al.  Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. , 2007, Cancer research.

[26]  Andrew Needles,et al.  Detecting vascular changes in tumour xenografts using micro-ultrasound and micro-ct following treatment with VEGFR-2 blocking antibodies. , 2007, Ultrasound in medicine & biology.

[27]  M. Dellian,et al.  Neovascular targeting chemotherapy: Encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature , 2004, International journal of cancer.

[28]  A. Haase,et al.  Snapshot flash mri. applications to t1, t2, and chemical‐shift imaging , 1990, Magnetic resonance in medicine.

[29]  David F Wilson,et al.  Calibration of oxygen-dependent quenching of the phosphorescence of Pd-meso-tetra (4-carboxyphenyl) porphine: a phosphor with general application for measuring oxygen concentration in biological systems. , 1996, Analytical biochemistry.

[30]  Dai Fukumura,et al.  Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. , 2007, Microvascular research.

[31]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[32]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[33]  L. Munn,et al.  Aberrant vascular architecture in tumors and its importance in drug-based therapies. , 2003, Drug discovery today.

[34]  J. Folkman.  Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[35]  A. Heerschap,et al.  Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization , 2008, Molecular Cancer Therapeutics.