Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy

Current clinical protocols favor a combination of antiangiogenic/antivascular compounds with classical chemotherapy. However, it remains unclear to what extent an antiangiogenic/antivascular therapy influences the delivery of chemotherapy. Therefore, the aim of the present study was to characterize the effects of the antiangiogenic tyrosine kinase inhibitor sunitinib on tumor microhemodynamics and delivery of chemotherapy. SF126 tumor cells were implanted subcutaneously into nude mice and were analyzed repeatedly by intravital microscopy. Treatment with sunitinib was initiated 7 days after implantation. To assess the effects of sunitinib on tumor vasculature and hemodynamics, we analyzed total and functional vessel densities, microvascular diameter, and microvascular blood flow rate. To study the delivery of chemotherapy, autofluorescent doxorubicin was systemically administered and its vascular delivery to the tumor tissue was quantified. Histological analysis included endothelial cell proliferation, pericyte coverage of tumor vessels, and tumor cell proliferation. Sunitinib significantly suppressed tumor growth by both antivascular and antiangiogenic effects. However, a number of tumor vessels escaped antiangiogenic therapy. Interestingly, in these surviving blood vessels sunitinib treatment resulted in an increased microvascular blood flow rate resulting in an improved delivery of chemotherapy via these blood vessels. Besides its potent antiangiogenic and antivascular efficacy, sunitinib treatment results in improved microhemodynamics and blood flow in tumor blood vessels that escape therapy leading to an improved vascular delivery of chemotherapy. These results provide the basis for a potential chemosensitizing effect of sunitinib. © 2008 Wiley‐Liss, Inc.

[1]  Sara M Weis,et al.  Vascular permeability in cardiovascular disease and cancer , 2008, Current opinion in hematology.

[2]  J. Gallo,et al.  Impact of Angiogenesis Inhibition by Sunitinib on Tumor Distribution of Temozolomide , 2008, Clinical Cancer Research.

[3]  Dominique,et al.  Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy , 2008, Clinical Cancer Research.

[4]  A. Gregory Sorensen,et al.  Angiogenesis in brain tumours , 2007, Nature Reviews Neuroscience.

[5]  R. Roskoski,et al.  Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. , 2007, Biochemical and biophysical research communications.

[6]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[7]  C. Antonescu,et al.  The Activity of Sunitinib against Gastrointestinal Stromal Tumor Seems to be Distinct from Its Antiangiogenic Effects , 2006, Clinical Cancer Research.

[8]  J. Desai,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[9]  R. Kerbel.  Antiangiogenic Therapy: A Universal Chemosensitization Strategy for Cancer? , 2006, Science.

[10]  Lee M Ellis,et al.  Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy , 2005, Cancer.

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

[12]  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.

[13]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[14]  Peter Vajkoczy,et al.  Combined inhibition of VEGF‐ and PDGF‐signaling enforces tumor vessel regression by interfering with pericyte‐mediated endothelial cell survival mechanisms , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[16]  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.

[17]  M. Menger,et al.  Characterization of Angiogenesis and Microcirculation of High–Grade Glioma: An Intravital Multifluorescence Microscopic Approach in the Athymic Nude Mouse , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  Beverly A. Teicher,et al.  A systems approach to cancer therapy , 1996, Cancer and Metastasis Reviews.

[19]  R K Jain,et al.  Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. , 1994, Cancer research.

[20]  G. Rosner,et al.  Measurement of material extravasation in microvascular networks using fluorescence video-microscopy. , 1993, Microvascular research.

[21]  Peter Vajkoczy,et al.  Vascular microenvironment in gliomas. , 2004, Cancer treatment and research.

[22]  D. Hallahan,et al.  The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels , 2004, Angiogenesis.

[23]  Juthamas Sukbuntherng,et al.  In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

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