Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy

Research article



The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange.

Materials and methods

3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy.


Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen.


VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product.


DCE-MRI Water exchange Tumor vascular volume and vascular permeability Combination antiangiogenic therapy 


  1. 1.
    O’Connor JP, Jackson A, Parker GJ, Jayson GC (2007) DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96:189–195PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Preda A, Novikov V, Moglich M, Turetschek K, Shames DM, Brasch RC, Cavagna FM, Roberts TP (2004) MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging 20:865–873PubMedCrossRefGoogle Scholar
  3. 3.
    Hylton N (2006) Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol 24:3293–3298PubMedCrossRefGoogle Scholar
  4. 4.
    Heilmann M, Kiessling F, Enderlin M, Schad LR (2006) Determination of pharmacokinetic parameters in DCE MRI: consequence of nonlinearity between contrast agent concentration and signal intensity. Invest Radiol 41:536–543PubMedCrossRefGoogle Scholar
  5. 5.
    Schabel MC, Parker DL (2008) Uncertainty and bias in contrast concentration measurements using spoiled gradient echo pulse sequences. Phys Med Biol 53:2345–2373PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Buckley DL, Parker GJ (2005) Measuring contrast agent concentration in T1-weighted dynamic contrast-enhanced MRI. In: Jackson A, Buckley DL, Parker GJ (eds) Dynamic contrast-enhanced magnetic resonance imaging in oncology, diagnostic imaging. Springer, Berlin, pp 69–79CrossRefGoogle Scholar
  7. 7.
    Donahue KM, Weisskoff RM, Chesler DA, Kwong KK, Bogdanov AA Jr, Mandeville JB, Rosen BR (1996) Improving MR quantification of regional blood volume with intravascular T1 contrast agents: accuracy, precision, and water exchange. Magn Reson Med 36:858–867PubMedCrossRefGoogle Scholar
  8. 8.
    Li X, Huang W, Rooney WD (2012) Signal-to-noise ratio, contrast-to-noise ratio and pharmacokinetic modeling considerations in dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 30:1313–1322PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Burstein HJ (2011) Bevacizumab for advanced breast cancer: all tied up with a RIBBON? J Clin Oncol 29:1232–1235PubMedCrossRefGoogle Scholar
  10. 10.
    Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, Rugo HS (2011) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29:4286–4293PubMedCrossRefGoogle Scholar
  11. 11.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  12. 12.
    Bahri S, Chen JH, Mehta RS, Carpenter PM, Nie K, Kwon SY, Yu HJ, Nalcioglu O, Su MY (2009) Residual breast cancer diagnosed by MRI in patients receiving neoadjuvant chemotherapy with and without bevacizumab. Ann Surg Oncol 16:1619–1628PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Bhujwalla ZM, Artemov D, Natarajan K, Ackerstaff E, Solaiyappan M (2001) Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts. Neoplasia 3:143–153PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y, Mori K, Fujimoto-Ouchi K (2010) Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer Drugs 21:687–694PubMedGoogle Scholar
  15. 15.
    Oku N, Doi K, Namba Y, Okada S (1994) Therapeutic effect of adriamycin encapsulated in long-circulating liposomes on Meth-A-sarcoma-bearing mice. Int J Cancer 58:415–419Google Scholar
  16. 16.
    Ogan MD, Schmiedl U, Moseley ME, Grodd W, Paajanen H, Brasch RC (1987) Albumin labeled with Gd-DTPA. An intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization. Invest Radiol 22:665–671PubMedCrossRefGoogle Scholar
  17. 17.
    Kato Y, Okollie B, Raman V, Vesuna F, Zhao M, Baker SD, Bhujwalla ZM, Artemov D (2007) Contributing factors of temozolomide resistance in MCF-7 tumor xenograft models. Cancer Biol Ther 6:891–897PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Levitt MH (1982) Symmetrical composite pulses for NMR population inversion. I. Compensation of radiofrequency field inhomogeneity. J Magn Reson 48:234–264Google Scholar
  19. 19.
    Bhujwalla ZM, Artemov D, Natarajan K, Solaiyappan M, Kollars P, Kristjansen PE (2003) Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin Cancer Res 9:355–362PubMedGoogle Scholar
  20. 20.
    Donahue KM, Burstein D, Manning WJ, Gray ML (1994) Studies of Gd-DTPA relaxivity and proton exchange rates in tissue. Magn Reson Med 32:66–76PubMedCrossRefGoogle Scholar
  21. 21.
    Vexler VS, Clement O, Schmitt-Willich H, Brasch RC (1994) Effect of varying the molecular weight of the MR contrast agent Gd-DTPA-polylysine on blood pharmacokinetics and enhancement patterns. J Magn Reson Imaging 4:381–388PubMedCrossRefGoogle Scholar
  22. 22.
    Blasberg RG, Fenstermacher JD, Patlak CS (1983) Transport of alpha-aminoisobutyric acid across brain capillary and cellular membranes. J Cereb Blood Flow Metab 3:8–32PubMedCrossRefGoogle Scholar
  23. 23.
    Chen H, Li F, Zhao X, Yuan C, Rutt B, Kerwin WS (2011) Extended graphical model for analysis of dynamic contrast-enhanced MRI. Magn Reson Med 66:868–878PubMedCrossRefGoogle Scholar
  24. 24.
    Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, Larsson HB, Lee TY, Mayr NA, Parker GJ, Port RE, Taylor J, Weisskoff RM (1999) Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 10:223–232PubMedCrossRefGoogle Scholar
  25. 25.
    Shames DM, Kuwatsuru R, Vexler V, Muhler A, Brasch RC (1993) Measurement of capillary permeability to macromolecules by dynamic magnetic resonance imaging: a quantitative noninvasive technique. Magn Reson Med 29:616–622PubMedCrossRefGoogle Scholar
  26. 26.
    Roberts HC, Roberts TP, Brasch RC, Dillon WP (2000) Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am J Neuroradiol 21:891–899PubMedGoogle Scholar
  27. 27.
    Windberger U, Bartholovitsch A, Plasenzotti R, Korak KJ, Heinze G (2003) Whole blood viscosity, plasma viscosity and erythrocyte aggregation in nine mammalian species: reference values and comparison of data. Exp Physiol 88:431–440PubMedCrossRefGoogle Scholar
  28. 28.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392PubMedGoogle Scholar
  29. 29.
    Bogin L, Degani H (2002) Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Res 62:1948–1951PubMedGoogle Scholar
  30. 30.
    Wall A, Persigehl T, Hauff P, Licha K, Schirner M, Muller S, von Wallbrunn A, Matuszewski L, Heindel W, Bremer C (2008) Differentiation of angiogenic burden in human cancer xenografts using a perfusion-type optical contrast agent (SIDAG). Breast Cancer Res BCR 10:R23CrossRefGoogle Scholar
  31. 31.
    Pathak AP, Artemov D, Ward BD, Jackson DG, Neeman M, Bhujwalla ZM (2005) Characterizing extravascular fluid transport of macromolecules in the tumor interstitium by magnetic resonance imaging. Cancer Res 65:1425–1432PubMedCrossRefGoogle Scholar
  32. 32.
    Cheng HL, Wright GA (2006) Rapid high-resolution T(1) mapping by variable flip angles: accurate and precise measurements in the presence of radiofrequency field inhomogeneity. Magn Reson Med 55:566–574PubMedCrossRefGoogle Scholar
  33. 33.
    Fournier LS, Novikov V, Lucidi V, Fu Y, Miller T, Floyd E, Shames DM, Brasch RC (2007) MR monitoring of cyclooxygenase-2 inhibition of angiogenesis in a human breast cancer model in rats. Radiology 243:105–111PubMedCrossRefGoogle Scholar
  34. 34.
    Sennino B, Raatschen HJ, Wendland MF, Fu Y, You WK, Shames DM, McDonald DM, Brasch RC (2009) Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP-Tag2 transgenic mice. Magn Reson Med 62:616–625PubMedCrossRefGoogle Scholar
  35. 35.
    Savai R, Langheinrich AC, Schermuly RT, Pullamsetti SS, Dumitrascu R, Traupe H, Rau WS, Seeger W, Grimminger F, Banat GA (2009) Evaluation of angiogenesis using micro-computed tomography in a xenograft mouse model of lung cancer. Neoplasia 11:48–56PubMedCentralPubMedGoogle Scholar
  36. 36.
    Kim E, Cebulla J, Ward BD, Rhie K, Zhang J, Pathak AP (2012) Assessing breast cancer angiogenesis in vivo: which susceptibility contrast MRI biomarkers are relevant. Magn Reson MedGoogle Scholar
  37. 37.
    Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071–1121PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Yu L, Wu X, Cheng Z, Lee CV, LeCouter J, Campa C, Fuh G, Lowman H, Ferrara N (2008) Interaction between bevacizumab and murine VEGF-A: a reassessment. Invest Ophthalmol Vis Sci 49:522–527PubMedCrossRefGoogle Scholar
  39. 39.
    Nagy JA, Dvorak HF (2012) Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets. Clin Exp Metastasis 29:657–662PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Goldfarb SB, Traina TA, Dickler MN (2010) Bevacizumab for advanced breast cancer. Womens Health (Lond Engl) 6:17–25CrossRefGoogle Scholar
  41. 41.
    Smith IE, Pierga JY, Biganzoli L, Cortes-Funes H, Thomssen C, Pivot X, Fabi A, Xu B, Stroyakovskiy D, Franke FA, Kaufman B, Mainwaring P, Pienkowski T, De Valk B, Kwong A, Gonzalez-Trujillo JL, Koza I, Petrakova K, Pereira D, Pritchard KI (2011) First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 22:595–602PubMedCrossRefGoogle Scholar
  42. 42.
    von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Muller BM, Denkert C, Loibl S, Nekljudova V, Untch M (2012) Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299–309CrossRefGoogle Scholar

Copyright information

© ESMRMB 2013

Authors and Affiliations

  1. 1.Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological ScienceJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations