The Role of Blood Pool Contrast Media in the Study of Tumor Pathophysiology

  • Laure S. Fournier
  • Robert C. Brasch
Part of the Medical Radiology book series (MEDRAD)


Magn Reson Image Permeability Surface Tumor Microvessels Blood Pool Contrast Agent Permeability Surface Area Product 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abolmaali ND, Hietschold V, Appold S et al (2002) Gadomer-17-enhanced 3D navigator-echo MR angiography of the pulmonary arteries in pigs. Eur Radiol 12:692–697PubMedGoogle Scholar
  2. Aicher KP, Dupon JW, White DL et al (1990) Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha. Cancer Res 50:7376–7381PubMedGoogle Scholar
  3. Allegrini P, Rudin M, Wood J et al (2002) Nvp-laf389 reduces tumor blood volume and vascular permeability in ca20948 pancreatic tumor model as measured in vivo by dynamic contrast enhanced MRI-putative surrogate markers for efficacy. In: International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, Hawaii, USAGoogle Scholar
  4. Baish JW, Jain RK (2000) Fractals and cancer. Cancer Res 60:3683–3688PubMedGoogle Scholar
  5. Bloom H, Richardson W (1957) Histologic grading and prognosis in breast cancer. Br J Cancer 11:359–377PubMedGoogle Scholar
  6. Bluemke DA, Stillman AE, Bis KG et al (2001) Carotid MR angiography: phase ii study of safety and efficacy for ms-325. Radiology 219:114–122PubMedGoogle Scholar
  7. Bonk RT, Schmiedl UP, Yuan C et al (2000) Time-of-flight MR angiography with Gd-DTPA hexamethylene diamine copolymer blood pool contrast agent: comparison of enhanced MRA and conventional angiography for arterial stenosis induced in rabbits. J Magn Reson Imaging 11:638–646CrossRefPubMedGoogle Scholar
  8. Brasch RC, Berthezene Y, Vexler V et al (1993) Pulmonary oxygen toxicity: Demonstration of abnormal capillary permeability using contrast-enhanced mri. Pediatr Radiol 23:495–500CrossRefPubMedGoogle Scholar
  9. Brasch RC, Li KC, Husband JE et al (2000) In vivo monitoring of tumor angiogenesis with MR imaging. Acad Radiol 7:812–823PubMedGoogle Scholar
  10. Cavagna F, Lorusso V, Anelli P et al (2001) Preclinical profile and clinical potential of gadocoletic acid trisodium salt (b-22956/1), a new intravascular contrast medium. Contrast Media Research, Capri, ItalyGoogle Scholar
  11. Cavagna F, La Noce A, Maggioni F et al (2002) Mr coronary angiography with the new intravascular contrast agent b-22956/1: first human experience. International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, Hawaii, USAGoogle Scholar
  12. Clement O, Pradel C, Siauve N et al (2001) Assessing perfusion and capillary permeability changes induced by a VEGF inhibitor in human tumor xenografts using macromolecular MR imaging contrast media. Contrast Media Research, Capri, ItalyGoogle Scholar
  13. Cohen F, Kuwatsuru R, Shames D et al (1995) Contrast enhanced MRI estimation of altered capillary permeability in experimental mammary carcinomas following x-irradiation. Invest Radiol 29:970–977Google Scholar
  14. Crone C (1963) The permeability of capillaries in various organs determined by the use of the “indicator diffusion” method. Acta Physiol Scand 58:292–305PubMedGoogle Scholar
  15. Crone C, Levitt DG (1984) Capillary permeability to small solutes. American Physiological Society, BethesdaGoogle Scholar
  16. Daldrup H, Shames DM, Wendland M et al (1998a) Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media. AJR Am J Roentgenol 171:941–949PubMedGoogle Scholar
  17. Daldrup HE, Shames DM, Husseini W et al (1998b) Quantification of the extraction fraction for gadopentetate across breast cancer capillaries. Magn Reson Med 40:537–543PubMedGoogle Scholar
  18. Daldrup-Link HE, Shames DM, Wendland M et al (2000) Comparison of gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging. Acad Radiol 7:934–944PubMedGoogle Scholar
  19. Daldrup-Link HE, Link TM, Moller HE et al (2001) Carboxymethyldextran-a2-Gd-DOTA enhancement patterns in the abdomen and pelvis in an animal model. Eur Radiol 11:1276–1284CrossRefPubMedGoogle Scholar
  20. Daldrup-Link HE, Kaiser A, Link TM et al (2002) Quantification of breast tumor microvascular permeabilities with Feruglose (Clariscan) enhanced MR-mammography: initial clinical trial. Ecr 2002. Eur Radiol [Suppl] 1:158Google Scholar
  21. Dvorak HF (1990) Leaky tumor vessels: consequences for tumor stroma generation and for solid tumor therapy. Prog Clin Biol ResGoogle Scholar
  22. Dvorak HF (2000) VPF/VEGF and the angiogenic response. Semin Perinatol 24:75–78PubMedGoogle Scholar
  23. Dvorak HF, Nagy JA, Dvorak JT et al (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133:95–109PubMedGoogle Scholar
  24. Eberhard A, Kahlert S, Goede V et al (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60:1388–1393PubMedGoogle Scholar
  25. Fenton BM, Beauchamp BK, Paoni SF et al (2001) Characterization of the effects of antiangiogenic agents on tumor pathophysiology. Am J Clin Oncol 24:453–457CrossRefPubMedGoogle Scholar
  26. Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71PubMedGoogle Scholar
  27. Gerlowski LE, Jain RK (1986) Microvascular permeability of normal and neoplastic tissues. Microvasc Res 31:288–305PubMedGoogle Scholar
  28. Gossmann A, Helbich T, Mesiano S et al (2000) Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor. Am J Obstet Gynecol 183:956–963CrossRefPubMedGoogle Scholar
  29. Gossmann A, Helbich TH, Kuriyama N et al (2002) Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme. J Magn Reson Imaging 15:233–240PubMedGoogle Scholar
  30. Grist TM, Korosec FR, Peters DC et al (1998) Steady-state and dynamic mr angiography with ms-325: initial experience in humans. Radiology 207:539–544Google Scholar
  31. Hashizume H, Baluk P, Morikawa S et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380PubMedGoogle Scholar
  32. Haunso S, Paaske WP, Sejrsen P et al (1980) Capillary permeability in canine myocardium as determined by bolus injection, residue detection. Acta Physiol Scand 108:389–397PubMedGoogle Scholar
  33. Helbich TH, Gossmann A, Mareski PA et al (2000) A new polysaccharide macromolecular contrast agent for MR imaging: biodistribution and imaging characteristics. J Magn Reson Imaging 11:694–701PubMedGoogle Scholar
  34. Henderson E, Sykes J, Drost D et al (2000) Simultaneous MRI measurement of blood flow, blood volume, and capillary permeability in mammary tumors using two different contrast agents. J Magn Reson Imaging 12:991–1003CrossRefPubMedGoogle Scholar
  35. Heuser LS, Miller FN (1986) Differential macromolecular leakage from the vasculature of tumors. Cancer 57:461–464PubMedGoogle Scholar
  36. Hoffmann U, Loewe C, Bernhard C et al (2002) MRA of the lower extremities in patients with pulmonary embolism using a blood pool contrast agent: Initial experience. J Magn Reson Imaging 15:429–437PubMedGoogle Scholar
  37. Hudgins PA, Anzai Y, Morris MR et al (2002) Ferumoxtran-10, a superparamagnetic iron oxide as a magnetic resonance enhancement agent for imaging lymph nodes: a phase 2 dose study. AJNR Am J Neuroradiol 23:649–656PubMedGoogle Scholar
  38. Jain R (1987) Transport of molecules across tumor vasculature. Cancer Metast Rev 6:559–593CrossRefGoogle Scholar
  39. Jain R (1988) Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658PubMedGoogle Scholar
  40. Jain R (1994) Barriers to drug delivery in solid tumors. Sci Am 271:58–65Google Scholar
  41. Jiang Y, Zhao JJ, Tang H et al (2002) Blood pool MR contrast media ms-325 improves contrast and disease characterization of rheumatoid arthritis for longitudinal quantification of inflamed synovium and joint fluid. International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, HI, USAGoogle Scholar
  42. Kauczor HU, Kreitner KF (2000) Contrast-enhanced MRI of the lung. Eur J Radiol 34:196–207CrossRefPubMedGoogle Scholar
  43. Kernstine KH, Stanford W, Mullan BF et al (1999) PET, CT, and MRI with combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg 68:1022–1028CrossRefPubMedGoogle Scholar
  44. Kroft LJ, de Roos A (1999) Blood pool contrast agents for cardiovascular MR imaging. J Magn Reson Imaging 10:395–403CrossRefPubMedGoogle Scholar
  45. Less JR, Skalak TC, Sevick EM et al (1991) Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res 51:265–273PubMedGoogle Scholar
  46. Li D, Dolan RP, Walovitch RC et al (1998) Three-dimensional MRI of coronary arteries using an intravascular contrast agent. Magn Reson Med 39:1014–1018PubMedGoogle Scholar
  47. Li D, Zheng J, Weinmann HJ (2001) Contrast-enhanced MR imaging of coronary arteries: comparison of intra-and extravascular contrast agents in swine. Radiology 218:670–678PubMedGoogle Scholar
  48. McDonald DM, Foss AJ (2000) Endothelial cells of tumor vessels: abnormal but not absent. Cancer Metastasis Rev 19:109–120CrossRefPubMedGoogle Scholar
  49. Nagy J, Brown L, Senger D et al (1989) Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 948:305–326PubMedGoogle Scholar
  50. Ogan MD (1988) Albumin labeled with Gd-DTPA: an intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization. Invest Radiol 23:961PubMedGoogle Scholar
  51. Okuhata Y, Brasch RC, Pham CD et al (1999) Tumor blood volume assays using contrast-enhanced magnetic resonance imaging: regional heterogeneity and postmortem artifacts. J Magn Reson Imaging 9:685–690CrossRefPubMedGoogle Scholar
  52. Petrovsky A, Weissleder R, Hu-Lowe D et al (2002) Non-invasive mr imaging of anti-angiogenic effects induced by a VEGF-RTKI in a human xenograft model. International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, HI, USAGoogle Scholar
  53. Pham C, Roberts T, van Bruggen N et al (1998) Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest 6:224–230Google Scholar
  54. Philippens M, Pikkemaat J, Schellekens S et al (2002) USPIO contrast enhanced MRI of irradiated rat spinal cord, monitoring macrophages and blood volume changes. International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, HI, USAGoogle Scholar
  55. Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210PubMedGoogle Scholar
  56. Roberts T, Kuretschek K, Preda A et al (2001) Tumor microvascular changes to anti-angiogenic treatment assessed by MR contrast media of different molecular weights. Contrast Media Research, Capri, ItalyGoogle Scholar
  57. Roberts T, Preda A, Turetschek K et al (2002) Permeability of b22956/1, a novel protein-binding contrast agent, resolves anti-angiogenic therapy in human breast cancer model. International Society for Magnetic Resonance in Medicine Tenth Scientific Meeting and Exhibition. Honolulu, HI, USAGoogle Scholar
  58. Scarff R, Torloni, H. (1968) Histological typing of breast tumors. World Health Organization, Geneva, pp 13–20Google Scholar
  59. Schmiedl U, Moseley ME, Ogan MD et al (1987) Comparison of initial biodistribution patterns of Gd-DTPA and albumin-(Gd-DTPA) using rapid spin echo MR imaging. J Comput Assist Tomogr 11:306–313PubMedGoogle Scholar
  60. Schwickert H, Stiskal M, van Dijke CF et al (1995) Tumor angiography using high-resolution, three-dimensional magnetic resonance imaging: comparison of gadopentetate dimeglumine and a macromolecular blood-pool contrast agent. Acad Radiol 2:851–858PubMedGoogle Scholar
  61. Schwickert H, Stiskal M, Roberts T et al (1996) Contrast-enhanced MRI assessment of tumor capillary permeability: the effect of pre-irradiation on the tumor delivery of chemotherapy. Radiology 198:893–898PubMedGoogle Scholar
  62. Sevick EM, Jain RK (1991) Measurement of capillary filtration coefficient in a solid tumor. Cancer Res 51:1352–1355PubMedGoogle Scholar
  63. St Lawrence KS, Lee TY (1998a) An adiabatic approximation to the tissue homogeneity model for water exchange in the brain. II. Experimental validation. J Cereb Blood Flow Metab 18:1378–1385CrossRefPubMedGoogle Scholar
  64. St Lawrence KS, Lee TY (1998b) An adiabatic approximation to the tissue homogeneity model for water exchange in the brain. I. Theoretical derivation. J Cereb Blood Flow Metab 18:1365–1377CrossRefPubMedGoogle Scholar
  65. Stuber M, Botnar RM, Danias PG et al (1999) Contrast agent-enhanced, free-breathing, three-dimensional coronary magnetic resonance angiography. J Magn Reson Imaging 10:790–799PubMedGoogle Scholar
  66. Su MY, Muhler A, Lao X et al (1998) Tumor characterization with dynamic contrast-enhanced MRI using MR contrast agents of various molecular weights. Magn Reson Med 39:259–269PubMedGoogle Scholar
  67. Su MY, Wang Z, Nalcioglu O (1999) Investigation of longitudinal vascular changes in control and chemotherapy-treated tumors to serve as therapeutic efficacy predictors. J Magn Reson Imaging 9:128–137CrossRefPubMedGoogle Scholar
  68. Svendsen JH, Efsen F, Haunso S (1992) Capillary permeability of 99mtc-dtpa and blood flow rate in the human myocardium determined by intracoronary bolus injection and residue detection. Cardiology 80:18–27PubMedGoogle Scholar
  69. Taupitz M, Schnorr J, Abramjuk C et al (2000) New generation of monomer-stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: preclinical results in rats and rabbits. J Magn Reson Imaging 12:905–911CrossRefPubMedGoogle Scholar
  70. Turetschek K, Floyd E, Helbich T et al (2001a) MRI assessment of microvascular characteristics in experimental breast tumors using a new blood pool contrast agent (ms-325) with correlations to histopathology. J Magn Reson Imaging 14:237–242PubMedGoogle Scholar
  71. Turetschek K, Floyd E, Shames DM et al (2001b) Assessment of a rapid clearance blood pool MR contrast medium (p792) for assays of microvascular characteristics in experimental breast tumors with correlations to histopathology. Magn Reson Med 45:880–886CrossRefPubMedGoogle Scholar
  72. Turetschek K, Preda A, Floyd E et al (2001c) MRI monitoring of tumor response to a novel VEGF tyrosine kinase inhibitor in an experimental breast cancer model. Contrast Media Research, Capri, ItalyGoogle Scholar
  73. Turetschek K, Roberts TP, Floyd E et al (2001d) Tumor microvascular characterization using ultrasmall superparamagnetic iron oxide particles (USPIO) in an experimental breast cancer model. J Magn Reson Imaging 13:882–888CrossRefPubMedGoogle Scholar
  74. Van Dijke CF, Brasch RC, Roberts TP et al (1996) Mammary carcinoma model: correlation of macromolecular contrast-enhanced MR imaging characterizations of tumor microvasculature and histologic capillary density. Radiology 198:813–818PubMedGoogle Scholar
  75. Varallyay P, Nesbit G, Muldoon LL et al (2002) Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors. AJNR Am J Neuroradiol 23:510–519PubMedGoogle Scholar
  76. Vexler V, Clèment O, Schmitt-Willich H et al (1994) Effect of varying molecular weight of the MR contrast agent Gd-DTPA-polylysine on blood pharmacokinetics and enhancement patterns. J Magn Reson Imag 4:381–388Google Scholar
  77. Weidner N (1995) Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat 36:169–180CrossRefPubMedGoogle Scholar
  78. Weinmann H-J, Brasch RC, Press WR et al (1984) Characteristics of gadolinium-DTPA complex: a potential MRI contrast agent. Am J Roentgenol 142:619–624Google Scholar
  79. Weissig VV, Babich J, Torchilin VV (2000) Long-circulating gadolinium-loaded liposomes: Potential use for magnetic resonance imaging of the blood pool. Colloids Surf B Biointerfaces 18:293–299CrossRefPubMedGoogle Scholar
  80. White D, Wang S-C, Aicher K et al (1989) Albumin-(DTPAGd) 15–20: Whole body clearance, and organ distribution of gadolinium. Society of Magnetic Resonance in Medicine, 8th Annual Meeting. Amsterdam, p 807Google Scholar
  81. Yuan F, Leunig M, Berk DA et al (1993) Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma ls174t using dorsal chamber in SCID mice. Microvasc Res 45:269–289CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Laure S. Fournier
    • 1
  • Robert C. Brasch
    • 1
  1. 1.Center for Pharmaceutical and Molecular Imaging, Department of RadiologyUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations