European Radiology

, Volume 22, Issue 4, pp 900–907 | Cite as

Dynamic contrast-enhanced micro-CT on mice with mammary carcinoma for the assessment of antiangiogenic therapy response

  • Fabian Eisa
  • Robert Brauweiler
  • Martin Hupfer
  • Tristan Nowak
  • Laura Lotz
  • Inge Hoffmann
  • David Wachter
  • Ralf Dittrich
  • Matthias W. Beckmann
  • Gregor Jost
  • Hubertus Pietsch
  • Willi A. Kalender
Molecular Imaging

Abstract

Objective

To evaluate the potential of in vivo dynamic contrast-enhanced micro-computed tomography (DCE micro-CT) for the assessment of antiangiogenic drug therapy response of mice with mammary carcinoma.

Methods

20 female mice with implanted MCF7 tumours were split into control group and therapy group treated with a known effective antiangiogenic drug. All mice underwent DCE micro-CT for the 3D analysis of functional parameters (relative blood volume [rBV], vascular permeability [K], area under the time-enhancement curve [AUC]) and morphology. All parameters were determined for total, peripheral and central tumour volumes of interest (VOIs). Immunohistochemistry was performed to characterise tumour vascularisation. 3D dose distributions were determined.

Results

The mean AUCs were significantly lower in therapy with P values of 0.012, 0.007 and 0.023 for total, peripheral and central tumour VOIs. K and rBV showed significant differences for the peripheral (PperK = 0.032, PperrBV = 0.029), but not for the total and central tumour VOIs (PtotalK = 0.108, PcentralK = 0.246, PtotalrBV = 0.093, PcentralrBV = 0.136). Mean tumour volume was significantly smaller in therapy (Pin vivo = 0.001, Pex vivo = 0.005). Histology revealed greater vascularisation in the controls and central tumour necrosis. Doses ranged from 150 to 300 mGy.

Conclusions

This study indicates the great potential of DCE micro-CT for early in vivo assessment of antiangiogenic drug therapy response.

Key Points

Dynamic contrast enhanced micro-CT (computed tomography) is a new experimental laboratory technique.

DCE micro-CT allows early in vivo assessment of antiangiogenic drug therapy response.

Pharmaceutical drugs can be tested before translation to clinical practice.

Both morphological and functional parameters can be obtained using DCE micro-CT.

Antiangiogenic effects can be visualised with DCE micro-CT.

Keywords

X-Ray Micro-CT Drug evaluation Preclinical Angiogenesis inhibitors Perfusion imaging Animals 

References

  1. 1.
    Du LY, Umoh J, Nikolov HN, Pollmann SI, Lee TY, Holdsworth DW (2007) A quality assurance phantom for the performance evaluation of volumetric micro-CT systems. Phys Med Biol 52:7087–7108PubMedCrossRefGoogle Scholar
  2. 2.
    Lee SC, Kim HK, Chun IK, Cho MH, Lee SY (2003) A flat-panel detector based micro-CT system: performance evaluation for small-animal imaging. Phys Med Biol 48:4173–4185PubMedCrossRefGoogle Scholar
  3. 3.
    Engelhorn T, Eyupoglu IY, Schwarz MA et al (2009) In vivo micro-CT imaging of rat brain glioma: a comparison with 3T MRI and histology. Neurosci Lett 458:28–31PubMedCrossRefGoogle Scholar
  4. 4.
    Ertel D, Kyriakou Y, Lapp RM, Kalender WA (2009) Respiratory phase-correlated micro-CT imaging of free-breathing rodents. Phys Med Biol 54:3837–3846PubMedCrossRefGoogle Scholar
  5. 5.
    Ritman EL (2004) Micro-computed tomography-current status and developments. Annu Rev Biomed Eng 6:185–208PubMedCrossRefGoogle Scholar
  6. 6.
    Ford NL, Thornton MM, Holdsworth DW (2003) Fundamental image quality limits for microcomputed tomography in small animals. Med Phys 30:2869–2877PubMedCrossRefGoogle Scholar
  7. 7.
    Kalender WA (2011) Computed tomography. Publicis Publishing, ErlangenGoogle Scholar
  8. 8.
    Kiessling F, Pichler JB (2011) Small animal imaging. Springer, Berlin HeidelbergCrossRefGoogle Scholar
  9. 9.
    Peyrin F, Salome M, Cloetens P, Laval-Jeantet AM, Ritman E, Ruegsegger P (1998) Micro-CT examinations of trabecular bone samples at different resolutions: 14, 7 and 2 micron level. Tech Health Care 6:391–401Google Scholar
  10. 10.
    Boyd SK, Davison P, Muller R, Gasser JA (2006) Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone 39:854–862PubMedCrossRefGoogle Scholar
  11. 11.
    Chun IK, Cho MH, Park JH, Lee SY (2006) In vivo trabecular thickness measurement in cancellous bones: longitudinal rat imaging studies. Physiol Meas 27:695–702PubMedCrossRefGoogle Scholar
  12. 12.
    Engelke K, Karolczak M, Lutz A, Seibert U, Schaller S, Kalender W (1999) Micro-CT. Technology and application for assessing bone structure. Radiologe 39:203–212PubMedCrossRefGoogle Scholar
  13. 13.
    Thali MJ, Taubenreuther U, Karolczak M et al (2003) Forensic microradiology: micro-computed tomography (Micro-CT) and analysis of patterned injuries inside of bone. J Forensic Sci 48:1336–1342PubMedGoogle Scholar
  14. 14.
    Wang X, Liu X, Niebur GL (2004) Preparation of on-axis cylindrical trabecular bone specimens using micro-CT imaging. J Biomech Eng 126:122–125PubMedCrossRefGoogle Scholar
  15. 15.
    Lerman A, Ritman EL (1999) Evaluation of microvascular anatomy by micro-CT. Herz 24:531–533PubMedCrossRefGoogle Scholar
  16. 16.
    Beighley PE, Thomas PJ, Jorgensen SM, Ritman EL (1997) 3D architecture of myocardial microcirculation in intact rat heart: a study with micro-CT. Adv Exp Med Biol 430:165–175PubMedCrossRefGoogle Scholar
  17. 17.
    Cavanaugh D, Johnson E, Price RE, Kurie J, Travis EL, Cody DD (2004) In vivo respiratory-gated micro-CT imaging in small-animal oncology models. Mol Imaging 3:55–62PubMedCrossRefGoogle Scholar
  18. 18.
    Kiessling F, Greschus S, Lichy MP et al (2004) Volumetric computed tomography (VCT): a new technology for noninvasive, high-resolution monitoring of tumor angiogenesis. Nat Med 10:1133–1138PubMedCrossRefGoogle Scholar
  19. 19.
    Namati E, Thiesse J, Sieren JC, Ross A, Hoffman EA, McLennan G (2010) Longitudinal assessment of lung cancer progression in the mouse using in vivo micro-CT imaging. Med Phys 37:4793–4805PubMedCrossRefGoogle Scholar
  20. 20.
    Wang Y, Wertheim DF, Jones AS, Coombes AG (2010) Micro-CT in drug delivery. Eur J Pharm Biopharm 74:41–49PubMedCrossRefGoogle Scholar
  21. 21.
    Wang Y, Wertheim DF, Jones AS, Chang HI, Coombes AG (2010) Micro-CT analysis of matrix-type drug delivery devices and correlation with protein release behaviour. J Pharm Sci 99:2854–2862PubMedGoogle Scholar
  22. 22.
    Rodriguez M, Zhou H, Keall P, Graves E (2009) Commissioning of a novel microCT/RT system for small animal conformal radiotherapy. Phys Med Biol 54:3727–3740PubMedCrossRefGoogle Scholar
  23. 23.
    Artaechevarria X, Blanco D, de Biurrun G et al (2011) Evaluation of micro-CT for emphysema assessment in mice: comparison with non-radiological techniques. Eur Radiol 21:954–962PubMedCrossRefGoogle Scholar
  24. 24.
    Postnov AA, Meurrens K, Weiler H et al (2005) In vivo assessment of emphysema in mice by high resolution X-ray microtomography. J Microsc 220:70–75PubMedCrossRefGoogle Scholar
  25. 25.
    Artaechevarria X, Perez-Martin D, Ceresa M et al (2009) Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT. Phys Med Biol 54:7009–7024PubMedCrossRefGoogle Scholar
  26. 26.
    Ford NL, Martin EL, Lewis JF, Veldhuizen RA, Holdsworth DW, Drangova M (2009) Quantifying lung morphology with respiratory-gated micro-CT in a murine model of emphysema. Phys Med Biol 54:2121–2130PubMedCrossRefGoogle Scholar
  27. 27.
    Johnson KA (2007) Imaging techniques for small animal imaging models of pulmonary disease: micro-CT. Toxicol Pathol 35:59–64PubMedCrossRefGoogle Scholar
  28. 28.
    Chen LC, Chang CH, Yu CY et al (2008) Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of (188)Re-DXR-liposome in C26 colon carcinoma ascites mice model. Nucl Med Biol 35:883–893PubMedCrossRefGoogle Scholar
  29. 29.
    Graves EE, Weissleder R, Ntziachristos V (2004) Fluorescence molecular imaging of small animal tumor models. Curr Mol Med 4:419–430PubMedCrossRefGoogle Scholar
  30. 30.
    Ho CL, Chen LC, Lee WC et al (2009) Receptor-binding, biodistribution, dosimetry, and micro-SPECT/CT imaging of 111In-[DTPA(1), Lys(3), Tyr(4)]-bombesin analog in human prostate tumor-bearing mice. Cancer Biother Radiopharm 24:435–443PubMedGoogle Scholar
  31. 31.
    Ritman EL (2002) Molecular imaging in small animals–roles for micro-CT. J Cell Biochem Suppl 39:116–124PubMedCrossRefGoogle Scholar
  32. 32.
    Badea CT, Johnston SM, Subashi E, Qi Y, Hedlund LW, Johnson GA (2009) Lung perfusion imaging in small animals using 4D micro-CT at heartbeat temporal resolution. Med Phys 37:54–62CrossRefGoogle Scholar
  33. 33.
    Eastwood JD, Provenzale JM, Hurwitz LM, Lee TY (2001) Practical injection-rate CT perfusion imaging: deconvolution-derived hemodynamics in a case of stroke. Neuroradiology 43:223–226PubMedCrossRefGoogle Scholar
  34. 34.
    Eastwood JD, Lev MH, Azhari T et al (2002) CT perfusion scanning with deconvolution analysis: pilot study in patients with acute middle cerebral artery stroke. Radiology 222:227–236PubMedCrossRefGoogle Scholar
  35. 35.
    Eastwood JD, Lev MH, Wintermark M et al (2003) Correlation of early dynamic CT perfusion imaging with whole-brain MR diffusion and perfusion imaging in acute hemispheric stroke. AJNR Am J Neuroradiol 24:1869–1875PubMedGoogle Scholar
  36. 36.
    Nabavi DG, Cenic A, Craen RA et al (1999) CT assessment of cerebral perfusion: experimental validation and initial clinical experience. Radiology 213:141–149PubMedGoogle Scholar
  37. 37.
    Klotz E, Koenig M (1999) Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke. Eur J Radiol 30:170–184PubMedCrossRefGoogle Scholar
  38. 38.
    Koenig M, Kraus M, Theek C, Klotz E, Gehlen W, Heuser L (2001) Quantitative assessment of the ischemic brain by means of perfusion-related parameters derived from perfusion CT. Stroke 32:431–437PubMedCrossRefGoogle Scholar
  39. 39.
    Koenig M, Banach-Planchamp R, Kraus M et al (2000) CT perfusion imaging in acute ischemic cerebral infarct: comparison of cerebral perfusion maps and conventional CT findings. Rofo 172:219–226CrossRefGoogle Scholar
  40. 40.
    Koenig M, Klotz E, Heuser L (2000) Cerebral perfusion CT: theoretical aspects, methodical implementation and clinical experience in the diagnosis of ischemic cerebral infarction. Rofo 172:210–218CrossRefGoogle Scholar
  41. 41.
    Badea CT, Drangova M, Holdsworth DW, Johnson GA (2008) In vivo small-animal imaging using micro-CT and digital subtraction angiography. Phys Med Biol 53:R319–350PubMedCrossRefGoogle Scholar
  42. 42.
    Kan Z, Kobayashi S, Phongkitkarun S, Charnsangavej C (2005) Functional CT quantification of tumor perfusion after transhepatic arterial embolization in a rat model. Radiology 237:144–150PubMedCrossRefGoogle Scholar
  43. 43.
    Kan Z, Phongkitkarun S, Kobayashi S et al (2005) Functional CT for quantifying tumor perfusion in antiangiogenic therapy in a rat model. Radiology 237:151–158PubMedCrossRefGoogle Scholar
  44. 44.
    Goh V, Halligan S, Gharpuray A, Wellsted D, Sundin J, Bartram CI (2008) Quantitative assessment of colorectal cancer tumor vascular parameters by using perfusion CT: influence of tumor region of interest. Radiology 247:726–732PubMedCrossRefGoogle Scholar
  45. 45.
    Ishii A, Korogi Y, Nishimura R et al (2004) Intraarterial infusion chemotherapy for head and neck cancers: evaluation of tumor perfusion with intraarterial CT during carotid arteriography. Radiat Med 22:254–259PubMedGoogle Scholar
  46. 46.
    Komemushi A, Tanigawa N, Kojima H, Kariya S, Sawada S (2003) CT perfusion of the liver during selective hepatic arteriography: pure arterial blood perfusion of liver tumor and parenchyma. Radiat Med 21:246–251PubMedGoogle Scholar
  47. 47.
    Sahani DV, Kalva SP, Hamberg LM et al (2005) Assessing tumor perfusion and treatment response in rectal cancer with multisection CT: initial observations. Radiology 234:785–792PubMedCrossRefGoogle Scholar
  48. 48.
    Sahani DV, Holalkere NS, Mueller PR, Zhu AX (2007) Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue–initial experience. Radiology 243:736–743PubMedCrossRefGoogle Scholar
  49. 49.
    Nett BE, Brauweiler R, Kalender W, Rowley H, Chen GH (2010) Perfusion measurements by micro-CT using prior image constrained compressed sensing (PICCS): initial phantom results. Phys Med Biol 55:2333–2350PubMedCrossRefGoogle Scholar
  50. 50.
    Tanaka C, O’Reilly T, Kovarik JM et al (2008) Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596–1602PubMedGoogle Scholar
  51. 51.
    O’Reilly T, McSheehy PM (2010) Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals. Transl Oncol 3:65–79PubMedGoogle Scholar
  52. 52.
    O’Reilly T, McSheehy PM, Kawai R et al (2010) Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. Canc Chemother Pharmacol 65:625–639CrossRefGoogle Scholar
  53. 53.
    Gennigens C, Sautois B, Jerusalem G (2010) Everolimus (RAD001/Afinitor) in the treatment of metastatic cell carcinoma. Rev Med Liege 65:212–216PubMedGoogle Scholar
  54. 54.
    Mastmeyer A, Engelke K, Fuchs C, Kalender WA (2006) A hierarchical 3D segmentation method and the definition of vertebral body coordinate systems for QCT of the lumbar spine. Med Image Anal 10:560–577PubMedCrossRefGoogle Scholar
  55. 55.
    Kang Y, Engelke K, Kalender WA (2003) A new accurate and precise 3-D segmentation method for skeletal structures in volumetric CT data. IEEE Trans Med Imaging 22:586–598PubMedCrossRefGoogle Scholar
  56. 56.
    Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7PubMedCrossRefGoogle Scholar
  57. 57.
    Miles KA, Griffiths MR (2003) Perfusion CT: a worthwhile enhancement? Br J Radiol 76:220–231PubMedCrossRefGoogle Scholar
  58. 58.
    Vermeulen PB, Gasparini G, Fox SB et al (2002) Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer 38:1564–1579PubMedCrossRefGoogle Scholar
  59. 59.
    Weidner N (1995) Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol 147:9–19PubMedGoogle Scholar
  60. 60.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324:1–8PubMedCrossRefGoogle Scholar
  61. 61.
    Fox SB, Harris AL (1997) Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy. Investig New Drugs 15:15–28CrossRefGoogle Scholar
  62. 62.
    Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Inst 94:883–893PubMedCrossRefGoogle Scholar
  63. 63.
    Purdie TG, Henderson E, Lee TY (2001) Functional CT imaging of angiogenesis in rabbit VX2 soft-tissue tumour. Phys Med Biol 46:3161–3175PubMedCrossRefGoogle Scholar
  64. 64.
    Carlson SK, Classic KL, Bender CE, Russell SJ (2007) Small animal absorbed radiation dose from serial micro-computed tomography imaging. Mol Imag Biol 9:78–82CrossRefGoogle Scholar
  65. 65.
    Bardelmeijer HA, Buckle T, Ouwehand M, Beijnen JH, Schellens JH, van Tellingen O (2003) Cannulation of the jugular vein in mice: a method for serial withdrawal of blood samples. Lab Anim 37:181–187PubMedCrossRefGoogle Scholar
  66. 66.
    Mokhtarian A, Meile MJ, Even PC (1993) Chronic vascular catheterization in the mouse. Physiol Behav 54:895–898PubMedCrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2011

Authors and Affiliations

  • Fabian Eisa
    • 1
    • 2
  • Robert Brauweiler
    • 1
  • Martin Hupfer
    • 1
  • Tristan Nowak
    • 1
  • Laura Lotz
    • 3
  • Inge Hoffmann
    • 3
  • David Wachter
    • 4
  • Ralf Dittrich
    • 3
  • Matthias W. Beckmann
    • 3
  • Gregor Jost
    • 5
  • Hubertus Pietsch
    • 5
  • Willi A. Kalender
    • 1
  1. 1.Institute of Medical PhysicsUniversity of Erlangen-NurembergErlangenGermany
  2. 2.Graduate School in Advanced Optical Technologies (SAOT)University of Erlangen-NurembergErlangenGermany
  3. 3.OB/GYN, University Hospital ErlangenUniversity of Erlangen-NurembergErlangenGermany
  4. 4.Institute of PathologyUniversity Hospital ErlangenErlangenGermany
  5. 5.Bayer Pharma AGBerlinGermany

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