Angiogenesis imaging with vascular-constrained particles: the why and how

  • Gregory M. Lanza
  • Shelton D. Caruthers
  • Patrick M. Winter
  • Michael S. Hughes
  • Anne H. Schmieder
  • Grace Hu
  • Samuel A. Wickline
Article

Abstract

Angiogenesis is a keystone in the treatment of cancer and potentially many other diseases. In cancer, first-generation antiangiogenic therapeutic approaches have demonstrated survival benefit in subsets of patients, but their high cost and notable adverse side effect risk have fueled alternative development efforts to personalize patient selection and reduce off-target effects. In parallel, rapid advances in cost-effective genomic profiling and sensitive early detection of high-risk biomarkers for cancer, atherosclerosis, and other angiogenesis-related pathologies will challenge the medical imaging community to identify, characterize, and risk stratify patients early in the natural history of these disease processes. Conventional diagnostic imaging techniques were not intended for such sensitive and specific detection, which has led to the emergence of novel noninvasive biomedical imaging approaches. The overall intent of molecular imaging is to achieve greater quantitative characterization of pathologies based on microanatomical, biochemical, or functional assessments; in many approaches, the capacity to deliver effective therapy, e.g., antiangiogenic therapy, can be combined. Agents with both diagnostic and therapy attributes have acquired the moniker “theranostics.” This review will explore biomedical imaging options being pursued to better segment and treat patients with angiogenesis-influenced disease using vascular-constrained contrast platform technologies.

Keywords

Molecular imaging Ultrasound MRI Microbubble Perfluorocarbon Nanoparticle Angiogenesis Fluorine-19 

References

  1. 1.
    Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007;8:464–78.PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005;333:328–35.PubMedCrossRefGoogle Scholar
  4. 4.
    Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 2007;12:713–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist 2007;12:356–61.PubMedCrossRefGoogle Scholar
  6. 6.
    Lang L. FDA approves sorafenib for patients with inoperable liver cancer. Gastroenterology 2008;134:379.Google Scholar
  7. 7.
    Rock EP, Goodman V, Jiang JX, Mahjoob K, Verbois SL, Morse D, et al. Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007;12:107–13.PubMedCrossRefGoogle Scholar
  8. 8.
    Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer 2006;42:3127–39.PubMedCrossRefGoogle Scholar
  9. 9.
    Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007;7:475–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, et al. AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 2007;25:319–27.PubMedCrossRefGoogle Scholar
  11. 11.
    Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 2005;23:5464–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 2005;92:1599–610.PubMedCrossRefGoogle Scholar
  13. 13.
    Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol 2006;24:3293–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Korpanty G, Carbon JG, Grayburn PA, Fleming JB, Brekken RA. Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature. Clin Cancer Res 2007;13:323–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Korpanty G, Grayburn PA, Shohet RV, Brekken RA. Targeting vascular endothelium with avidin microbubbles. Ultrasound Med Biol 2005;31:1279–83.PubMedCrossRefGoogle Scholar
  16. 16.
    Korpanty G, Chen S, Shohet RV, Ding J, Yang B, Frenkel PA, et al. Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles. Gene Ther 2005;12:1305–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Pochon S, Tardy I, Bussat P, Bettinger T, Brochot J, von Wronski M, et al. BR55: a lipopeptide-based VEGFR2-targeted ultrasound contrast agent for molecular imaging of angiogenesis. Invest Radiol 2010;45:89–95.PubMedCrossRefGoogle Scholar
  18. 18.
    De Nichilo M, Burns G. Granulocyte-macrophage and macrophage colony-stimulating factors differentially regulate alpha v integrin expression on cultured human macrophages. Proc Natl Acad Sci USA 1993;90:2517–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Helluin O, Chan C, Vilaire G, Mousa S, DeGrado WF, Bennett JS. The activation state of alpha v beta 3 regulates platelet and lymphocyte adhesion to intact and thrombin-cleaved osteopontin. J Biol Chem 2000;275:18337–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Itoh H, Nelson P, Mureebe L, Horowitz A, Kent K. The role of integrins in saphenous vein vascular smooth muscle cell migration. J Vasc Surg 1997;25:1061–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Carreiras F, Denoux Y, Staedel C, Lehmann M, Sichel F, Gauduchon P. Expression and localization of alpha v integrins and their ligand vitronectin in normal ovarian epithelium and in ovarian carcinoma. Gynecol Oncol 1996;62:260–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Kageshita T, Hamby CV, Hirai S, Kimura T, Ono T, Ferrone S. Differential clinical significance of alpha(v)beta(3) expression in primary lesions of acral lentiginous melanoma and of other melanoma histotypes. Int J Cancer 2000;89:153–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Weissleder R, Bogdanov Jr A, Tung CH, Weinmann HJ. Size optimization of synthetic graft copolymers for in vivo angiogenesis imaging. Bioconjug Chem 2001;12:213–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Leong-Poi H, Christiansen J, Klibanov AL, Kaul S, Lindner JR. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation 2003;107:455–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Ellegala DB, Leong-Poi H, Carpenter JE, Klibanov AL, Kaul S, Shaffrey ME, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3. Circulation 2003;108:336–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Lindner JR, Song J, Christiansen J, Klibanov AL, Xu F, Ley K. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation 2001;104:2107–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Kaufmann BA, Sanders JM, Davis C, Xie A, Aldred P, Sarembock IJ, et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 2007;116:276–84.PubMedCrossRefGoogle Scholar
  28. 28.
    Mattrey RF. The potential role of perfluorochemicals (PFCs) in diagnostic imaging. Artif Cells Blood Substit Immobil Biotechnol 1994;22:295–313.PubMedCrossRefGoogle Scholar
  29. 29.
    Mattrey R, Scheible F, Gosink B, Leopold G, Long D, Higgins C. Perfluoroctylbromide: a liver/spleen-specific and tumor-imaging ultrasound contrast material. Radiology 1982;145:759–62.PubMedGoogle Scholar
  30. 30.
    Lanza GM, Wallace KD, Scott MJ, Cacheris WP, Abendschein DR, Christy DH, et al. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 1996;94:3334–40.PubMedGoogle Scholar
  31. 31.
    Lanza GM, Trousil RL, Wallace KD, Rose JH, Hall CS, Scott MJ, et al. In vitro characterization of a novel, tissue-targeted ultrasonic contrast system with acoustic microscopy. J Acoust Soc Am 1998;104:3665–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Hughes MS, McCarthy JE, Marsh JN, Arbeit JM, Neumann RG, Fuhrhop RW, et al. Properties of an entropy-based signal receiver with an application to ultrasonic molecular imaging. J Acoust Soc Am 2007;121:3542–57.PubMedCrossRefGoogle Scholar
  33. 33.
    Hughes MS, Marsh JN, Arbeit JM, Neumann RG, Fuhrhop RW, Wallace KD, et al. Application of Renyi entropy for ultrasonic molecular imaging. J Acoust Soc Am 2009;125:3141–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Hughes M, Marsh J, Hall C, Allen J, Brown P, Lacy E, et al. In vivo ultrasonic detection of angiogenesis with site-targeted nanoparticle contrast agents using measure-theoretic signal receivers. Ultrason Symp 2004;2:1106–9.Google Scholar
  35. 35.
    Bekeredjian R, Chen S, Pan W, Grayburn PA, Shohet RV. Effects of ultrasound-targeted microbubble destruction on cardiac gene expression. Ultrasound Med Biol 2004;30:539–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Bekeredjian R, Chen S, Frenkel PA, Grayburn PA, Shohet RV. Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart. Circulation 2003;108:1022–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Chen S, Ding JH, Bekeredjian R, Yang BZ, Shohet RV, Johnston SA, et al. Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology. Proc Natl Acad Sci USA 2006;103:8469–74.PubMedCrossRefGoogle Scholar
  38. 38.
    Chai R, Chen S, Ding J, Grayburn PA. Efficient, glucose responsive and islet-specific transgene expression by a modified rat insulin promoter. Gene Ther 2009;16:1202–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen S, Ding J, Yu C, Yang B, Wood DR, Grayburn PA. Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1. Gene Ther 2007;14:1102–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Leong-Poi H, Kuliszewski MA, Lekas M, Sibbald M, Teichert-Kuliszewska K, Klibanov AL, et al. Therapeutic arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle. Circ Res 2007;101:295–303.PubMedCrossRefGoogle Scholar
  41. 41.
    Chappell JC, Song J, Burke CW, Klibanov AL, Price RJ. Targeted delivery of nanopartides bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis. Small 2008;4:1769–77.PubMedCrossRefGoogle Scholar
  42. 42.
    Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 2005;24:12–20.PubMedCrossRefGoogle Scholar
  43. 43.
    Lanza GM, Lorenz CH, Fischer SE, Scott MJ, Cacheris WP, Kaufmann RJ, et al. Enhanced detection of thrombi with a novel fibrin-targeted magnetic resonance imaging agent. Acad Radiol 1998;5 Suppl 1:S173–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KC. Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. Nat Med 1998;4:623–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Schmieder A, Winter P, Caruthers S, Harris T, Williams T, Allen J, et al. MR molecular imaging of melanoma angiogenesis with ανβ3-targeted paramagnetic nanoparticles. Magn Reson Med 2005;53:621–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Mulder WJ, Strijkers GJ, Habets JW, Bleeker EJ, van der Schaft DW, Storm G, et al. MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle. FASEB J 2005;19:2008–10.PubMedGoogle Scholar
  47. 47.
    Mulder WJ, van der Schaft DW, Hautvast PA, Strijkers GJ, Koning GA, Storm G, et al. Early in vivo assessment of angiostatic therapy efficacy by molecular MRI. FASEB J 2007;21:378–83.PubMedCrossRefGoogle Scholar
  48. 48.
    Pike MM, Stoops CN, Langford CP, Akella NS, Nabors LB, Gillespie GY. High-resolution longitudinal assessment of flow and permeability in mouse glioma vasculature: sequential small molecule and SPIO dynamic contrast agent MRI. Magn Reson Med 2009;61:615–25.PubMedCrossRefGoogle Scholar
  49. 49.
    Nijdam AJ, Nicholson III TR, Shapiro JP, Smith BR, Heverhagen JT, Schmalbrock P, et al. Nanoparticulate iron oxide contrast agents for untargeted and targeted cardiovascular magnetic resonance imaging. Curr Nanosci 2009;5:88–102.CrossRefGoogle Scholar
  50. 50.
    Hyodo F, Chandramouli GVR, Matsumoto S, Matsumoto KI, Mitchell JB, Krishna MC, et al. Estimation of tumor microvessel density by MRI using a blood pool contrast agent. Int J Oncol 2009;35:797–804.PubMedGoogle Scholar
  51. 51.
    Gambarota G, Leenders W, Maass C, Wesseling P, van der Kogel B, van Tellingen O, et al. Characterisation of tumour vasculature in mouse brain by USPIO contrast-enhanced MRI. Br J Cancer 2008;98:1784–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Beaumont M, Lemasson B, Farion R, Segebarth C, Rémy C, Barbier EL. Characterization of tumor angiogenesis in rat brain using iron-based vessel size index MRI in combination with gadolinium-based dynamic contrast-enhanced MRI. J Cereb Blood Flow Metab 2009;29:1714–26.PubMedCrossRefGoogle Scholar
  53. 53.
    Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, et al. Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 2003;228:480–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Anderson SA, Glod J, Arbab AS, Noel M, Ashari P, Fine HA, et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005;105:420–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Kelly KA, Allport JR, Tsourkas A, Shinde-Patil VR, Josephson L, Weissleder R. Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle. Circ Res 2005;96:327–36.PubMedCrossRefGoogle Scholar
  56. 56.
    Stuber M, Gilson WD, Schär M, Kedziorek DA, Hofmann LV, Shah S, et al. Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with ON-resonant water suppression (IRON). Magn Reson Med 2007;58:1072–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Senpan A, Caruthers S, Rhee I, Mauro N, Pan D, Hu G, et al. Conquering the dark side: colloidal iron oxide nanoparticles. ACS Nano 2009;3(12):3917–26.PubMedCrossRefGoogle Scholar
  58. 58.
    Bachert P. Pharmacokinetics using fluorine NMR in vivo. Prog Nucl Magn Reson Spectrosc 1998;33:1–56.CrossRefGoogle Scholar
  59. 59.
    Yu X, Song SK, Scott MJ, Fuhrhop RJ, Lanza GM, Hall CS, et al. Molecular characterization of thrombus using bimodal 1H/19F MR imaging with a novel fibrin-targeted nanoparticulate contrast agent. Proc Int Soc Magn Reson Med 2000;8:465.Google Scholar
  60. 60.
    Morawski AM, Winter PM, Yu X, Fuhrhop RW, Scott MJ, Hockett F, et al. Quantitative “magnetic resonance immunohistochemistry” with ligand-targeted (19)F nanoparticles. Magn Reson Med 2004;52:1255–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Caruthers SD, Neubauer AM, Hockett FD, Lamerichs R, Winter PM, Scott MJ, et al. In vitro demonstration using (19)F magnetic resonance to augment molecular imaging with paramagnetic perfluorocarbon nanoparticles at 1.5 Tesla. Invest Radiol 2006;41:305–12.PubMedCrossRefGoogle Scholar
  62. 62.
    Waters EA, Chen J, Allen JS, Zhang H, Lanza GM, Wickline SA. Detection and quantification of angiogenesis in experimental valve disease with integrin-targeted nanoparticles and 19-fluorine MRI/MRS. J Cardiovasc Magn Reson 2008;10:43.PubMedCrossRefGoogle Scholar
  63. 63.
    Waters EA, Chen J, Yang X, Zhang H, Neumann R, Santeford A, et al. Detection of targeted perfluorocarbon nanoparticle binding using 19F diffusion weighted MR spectroscopy. Magn Reson Med 2008;60:1232–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Rahmer J, Keupp J, Caruthers S, Lips O, Williams T, Wickline S, et al. 19F/1H simultaneous 3D radial imaging of atherosclerotic rabbits using self-navigated respiratory motion compensation. Proc Int Soc Magn Reson Med 2009;4611.Google Scholar
  65. 65.
    Rahmer J, Keupp J, Caruthers S, Lips O, Williams T, Wickline S, et al. Dual resolution simultaneous 19F/1H in vivo imaging of targeted nanoparticles. Proc Int Soc Magn Reson Med 2009;611.Google Scholar
  66. 66.
    Keupp J, Caruthers S, Rahmer J, Williams T, Wickline S, Lanza G, et al. Fluorine-19 MR molecular imaging of angiogenesis on Vx-2 tumors in rabbits using ανβ3-targeted nanoparticles. Proc Int Soc Magn Reson Med 2009;223.Google Scholar
  67. 67.
    Lanza G, Yu X, Winter P, Abendschein D, Karukstis K, Scott M, et al. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 2002;106:2842–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Soman N, Lanza G, Heuser J, Schlesinger P, Wickline S. Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides. Nano Lett 2008;8:1131–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Crowder KC, Hughes MS, Marsh JN, Barbieri AM, Fuhrhop RW, Lanza GM, et al. Sonic activation of molecularly-targeted nanoparticles accelerates transmembrane lipid delivery to cancer cells through contact-mediated mechanisms: implications for enhanced local drug delivery. Ultrasound Med Biol 2005;31:1693–700.PubMedCrossRefGoogle Scholar
  70. 70.
    Cyrus T, Zhang H, Allen JS, Williams TA, Hu G, Caruthers SD, et al. Intramural delivery of rapamycin with alphavbeta3-targeted paramagnetic nanoparticles inhibits stenosis after balloon injury. Arterioscler Thromb Vasc Biol 2008;28:820–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Winter P, Neubauer A, Caruthers S, Harris T, Robertson J, Williams T, et al. Endothelial alpha(ν)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol 2006;26:2103–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Schmieder AH, Caruthers SD, Zhang H, Williams TA, Robertson JD, Wickline SA, et al. Three-dimensional MR mapping of angiogenesis with {alpha}5{beta}1({alpha}{nu}{beta}3)-targeted theranostic nanoparticles in the MDA-MB-435 xenograft mouse model. FASEB J 2008;22:4179–89.PubMedCrossRefGoogle Scholar
  73. 73.
    Winter P, Caruthers S, Zhang H, Williams T, Wickline S, Lanza G. Antiangiogenic synergism of integrin-targeted fumagillin nanoparticles and atorvastatin in atherosclerosis. JACC Cardiovasc Imaging 2008;1:624–34.PubMedCrossRefGoogle Scholar
  74. 74.
    Winter PM, Schmieder AH, Caruthers SD, Keene JL, Zhang H, Wickline SA, et al. Minute dosages of alpha(nu)beta3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits. FASEB J 2008;22:2758–67.PubMedCrossRefGoogle Scholar
  75. 75.
    Soman N, Baldwin S, Hu G, Marsh J, Lanza G, Heuser J, et al. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. J Clin Invest 2009;119:2830–42.PubMedCrossRefGoogle Scholar
  76. 76.
    Marsh J, Senpan A, Hu G, Scott M, Gaffney P, Wickline S, et al. Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis. Nanomedicine 2007;2:533–43.PubMedCrossRefGoogle Scholar
  77. 77.
    Liu S, Widom J, Kemp CW, Crews CM, Clardy J. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 1998;282:1324–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci USA 1997;94:6099–103.PubMedCrossRefGoogle Scholar
  79. 79.
    Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 1999;284:808–12.PubMedCrossRefGoogle Scholar
  80. 80.
    Castronovo V, Belotti D. TNP-470 (AGM-1470): mechanisms of action and early clinical development. Eur J Cancer 1996;32A:2520–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Konno H, Tanaka T, Kanai T, Maruyama K, Nakamura S, Baba S. Efficacy of an angiogenesis inhibitor, TNP-470, in xenotransplanted human colorectal cancer with high metastatic potential. Cancer 1996;77:1736–40.PubMedGoogle Scholar
  82. 82.
    Shusterman S, Grupp SA, Barr R, Carpentieri D, Zhao H, Maris JM. The angiogenesis inhibitor TNP-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease. Clin Cancer Res 2001;7:977–84.PubMedGoogle Scholar
  83. 83.
    Bhargava P, Marshall JL, Rizvi N, Dahut W, Yoe J, Figuera M, et al. A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. Clin Cancer Res 1999;5:1989–95.PubMedGoogle Scholar
  84. 84.
    Kudelka AP, Verschraegen CF, Loyer E. Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N Engl J Med 1998;338:991–2.PubMedCrossRefGoogle Scholar
  85. 85.
    Kudelka AP, Levy T, Verschraegen CF, Edwards CL, Piamsomboon S, Termrungruanglert W, et al. A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res 1997;3:1501–5.PubMedGoogle Scholar
  86. 86.
    Logothetis CJ, Wu KK, Finn LD, Daliani D, Figg W, Ghaddar H, et al. Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer. Clin Cancer Res 2001;7:1198–203.PubMedGoogle Scholar
  87. 87.
    Offodile R, Walton T, Lee M, Stiles A, Nguyen M. Regression of metastatic breast cancer in a patient treated with the anti-angiogenic drug TNP-470. Tumori 1999;85:51–3.PubMedGoogle Scholar
  88. 88.
    Griffioen AW, Tromp SC, Hillen HF. Angiogenesis modulates the tumour immune response. Int J Exp Pathol 1998;79:363–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Griffioen AW, Relou IA, Gallardo Torres HI, Damen CA, Martinotti S, De Graaf JC, et al. The angiogenic factor bFGF impairs leukocyte adhesion and rolling under flow conditions. Angiogenesis 1998;2:235–43.PubMedCrossRefGoogle Scholar
  90. 90.
    Griffioen AW, Damen CA, Mayo KH, Barendsz-Janson AF, Martinotti S, Blijham GH, et al. Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. Int J Cancer 1999;80:315–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res 1996;56:1111–7.PubMedGoogle Scholar
  92. 92.
    Griffioen AW, Damen CA, Blijham GH, Groenewegen G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 1996;88:667–73.PubMedGoogle Scholar
  93. 93.
    Kim S, Harris M, Varner J. Regulation of integrin alpha vbeta 3-mediated endothelial cell migration and angiogenesis by integrin alpha5beta1 and protein kinase A. J Biol Chem 2000;275:33920–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Boudreau N, Varner J. The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. J Biol Chem 2004;279:4862–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Moreno PR, Purushothaman KR, Fuster V, Echeverri D, Truszczynska H, Sharma SK, et al. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability. Circulation 2004;110:2032–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation 2006;113:2245–52.PubMedCrossRefGoogle Scholar
  97. 97.
    Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054–61.PubMedCrossRefGoogle Scholar
  98. 98.
    Björnheden T, Levin M, Evaldsson M, Wiklund O. Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler Thromb Vasc Biol 1999;19:870–6.PubMedGoogle Scholar
  99. 99.
    Boyle JJ, Wilson B, Bicknell R, Harrower S, Weissberg PL, Fan TP. Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J Pathol 2000;192:234–42.PubMedCrossRefGoogle Scholar
  100. 100.
    Khatri JJ, Johnson C, Magid R, Lessner SM, Laude KM, Dikalov SI, et al. Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma. Circulation 2004;109:520–5.PubMedCrossRefGoogle Scholar
  101. 101.
    de Boer OJ, van der Wal AC, Teeling P, Becker AE. Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularization? Cardiovasc Res 1999;41:443–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Kolodgi F, Narula J, Yuan C, Finn A, Gold H, Virmani R. Eliminating plaque angiogenesis: reply. J Am Coll Cardiol 2007;50:1521.CrossRefGoogle Scholar
  103. 103.
    Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 2005;112:1813–24.PubMedCrossRefGoogle Scholar
  104. 104.
    Jain RK, Finn AV, Kolodgie FD, Gold HK, Virmani R. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat Clin Pract Cardiovasc Med 2007;4:491–502.PubMedCrossRefGoogle Scholar
  105. 105.
    Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 2003;108:2270–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Sukhova GK, Williams JK, Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol 2002;22:1452–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Koutouzis M, Nomikos A, Nikolidakis S, Tzavara V, Andrikopoulos V, Nikolaou N, et al. Statin treated patients have reduced intraplaque angiogenesis in carotid endarterectomy specimens. Atherosclerosis 2007;192:457–63.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Gregory M. Lanza
    • 1
  • Shelton D. Caruthers
    • 1
  • Patrick M. Winter
    • 1
  • Michael S. Hughes
    • 1
  • Anne H. Schmieder
    • 1
  • Grace Hu
    • 1
  • Samuel A. Wickline
    • 1
  1. 1.Division of CardiologyWashington University Medical SchoolSt. LouisUSA

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