European Radiology

, Volume 20, Issue 8, pp 2013–2026 | Cite as

Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours

  • Huaijun Wang
  • Junjie Li
  • Feng Chen
  • Frederik De Keyzer
  • Jie Yu
  • Yuanbo Feng
  • Johan Nuyts
  • Guy Marchal
  • Yicheng Ni
Magnetic Resonance



To evaluate effects of a vascular-disrupting agent on rodent tumour models.


Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [18F]fluorodeoxyglucose micro-positron emission tomography (18F-FDG µPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUVmax) from FDG µPET were quantified and correlated with postmortem microangiography and histopathology.


In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUVmax dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05).


The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.


ZD6126 Magnetic resonance imaging (MRI) Positron emission tomography (PET) Tumour Liver Imaging biomarkers 



This work was partially supported by the grants awarded by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO Vlaanderen) Impulsfinanciering project (ZWAP/05/018), Geconcerteerde Onderzoeksactie (GOA) of the Flemish Government, OT project (OT/06/70) MoSAIC, the K.U. Leuven Molecular Small Animal Imaging Center (KUL EF/05/08) and a EU project Asia-Link CfP 2006-EuropeAid/123738/C/ACT/Multi-Proposal No. 128-498/111.


  1. 1.
    Smith JJ, Sorensen AG, Thrall JH (2003) Biomarkers in imaging: realizing radiology’s future. Radiology 227:633–638CrossRefPubMedGoogle Scholar
  2. 2.
    Padhani AR, Liu G, Mu-Koh D, Chenevert TL, Thoeny HC, Takahara T, Dzik-Jurasz A, Ross BD, Van Cauteren M, Collins D, Hammoud DA, Rustin GJ, Taouli B, Choyke PL (2009) Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 11:102–125PubMedGoogle Scholar
  3. 3.
    Colburn WA (2003) Biomarkers in drug discovery and development: from target identification through drug marketing. J Clin Pharmacol 43:329–341CrossRefPubMedGoogle Scholar
  4. 4.
    US FDA (2009) Medical imaging and drug development. Accessed 17 Sept 2009
  5. 5.
    Park JW, Kerbel RS, Kelloff GJ, Barrett JC, Chabner BA, Parkinson DR, Peck J, Ruddon RW, Sigman CC, Slamon DJ (2004) Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development. Clin Cancer Res 10:3885–3896CrossRefPubMedGoogle Scholar
  6. 6.
    Jain KK (2007) Cancer biomarkers: current issues and future directions. Curr Opin Mol Ther 9:563–571PubMedGoogle Scholar
  7. 7.
    Kleespies A, Kohl G, Friedrich M, Ryan AJ, Barge A, Jauch KW, Bruns CJ (2005) Vascular targeting in pancreatic cancer: the novel tubulin-binding agent ZD6126 reveals antitumor activity in primary and metastatic tumor models. Neoplasia 7:957–966CrossRefPubMedGoogle Scholar
  8. 8.
    Evelhoch JL, LoRusso PM, He Z, DelProposto Z, Polin L, Corbett TH, Langmuir P, Wheeler C, Stone A, Leadbetter J, Ryan AJ, Blakey DC, Waterton JC (2004) Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 10:3650–3657CrossRefPubMedGoogle Scholar
  9. 9.
    Beerepoot LV, Radema SA, Witteveen EO, Thomas T, Wheeler C, Kempin S, Voest EE (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491–1498CrossRefPubMedGoogle Scholar
  10. 10.
    Gotlieb AI (1990) The endothelial cytoskeleton: organization in normal and regenerating endothelium. Toxicol Pathol 18:603–617PubMedGoogle Scholar
  11. 11.
    Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60:1388–1393PubMedGoogle Scholar
  12. 12.
    Hermens AF, Barendsen GW (1967) Cellular proliferation patterns in an experimental rhabdomyosarcoma in the rat. Eur J Cancer 3:361–369PubMedGoogle Scholar
  13. 13.
    Chen F, Sun X, De Keyzer F, Yu J, Peeters R, Coudyzer W, Vandecaveye V, Landuyt W, Bosmans H, Van Hecke P, Marchal G, Ni Y (2006) Liver tumor model with implanted rhabdomyosarcoma in rats: MR imaging, microangiography, and histopathologic analysis. Radiology 239:554–562CrossRefPubMedGoogle Scholar
  14. 14.
    Madhu B, Waterton JC, Griffiths JR, Ryan AJ, Robinson SP (2006) The response of RIF-1 fibrosarcomas to the vascular-disrupting agent ZD6126 assessed by in vivo and ex vivo 1H magnetic resonance spectroscopy. Neoplasia 8:560–567CrossRefPubMedGoogle Scholar
  15. 15.
    Thoeny HC, De Keyzer F, Chen F, Ni Y, Landuyt W, Verbeken EK, Bosmans H, Marchal G, Hermans R (2005) Diffusion-weighted MR imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats. Radiology 234:756–764CrossRefPubMedGoogle Scholar
  16. 16.
    Wang H, Sun X, Chen F, De Keyzer F, Yu J, Landuyt W, Vandecaveye V, Peeters R, Bosmans H, Hermans R, Marchal G, Ni Y (2009) Treatment of rodent liver tumor with combretastatin A4 phosphate: noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology. Invest Radiol 44:44–53CrossRefPubMedGoogle Scholar
  17. 17.
    Hudson HM, Larkin RS (1994) Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans Med Imaging 13:601–609CrossRefPubMedGoogle Scholar
  18. 18.
    Feldkamp LA, Davis LC, Kress JW (1984) Practical cone-beam algorithm. J Opt Soc Am A 1:612–619CrossRefGoogle Scholar
  19. 19.
    Thoeny HC, De Keyzer F, Vandecaveye V, Chen F, Sun X, Bosmans H, Hermans R, Verbeken EK, Boesch C, Marchal G, Landuyt W, Ni Y (2005) Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging. Radiology 237:492–499CrossRefPubMedGoogle Scholar
  20. 20.
    Tofts PS, Berkowitz BA (1993) Rapid measurement of capillary permeability using the early part of the dynamic Gd-DTPA MRI enhancement curve. J Magn Reson B 102:129–136CrossRefGoogle Scholar
  21. 21.
    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 10:223–232CrossRefPubMedGoogle Scholar
  22. 22.
    Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 7:91–101CrossRefPubMedGoogle Scholar
  23. 23.
    Brepoels L, Stroobants S, Vandenberghe P, Spaepen K, Dupont P, Nuyts J, Bormans G, Mortelmans L, Verhoef G, De Wolf-Peeters C (2007) Effect of corticosteroids on 18F-FDG uptake in tumor lesions after chemotherapy. J Nucl Med 48:390–397PubMedGoogle Scholar
  24. 24.
    Paquet N, Albert A, Foidart J, Hustinx R (2004) Within-patient variability of 18F-FDG: standardized uptake values in normal tissues. J Nucl Med 45:784–788PubMedGoogle Scholar
  25. 25.
    Eng J (2004) Sample size estimation: how many individuals should be studied? Radiology 227:309–313CrossRefGoogle Scholar
  26. 26.
    McIntyre DJ, Robinson SP, Howe FA, Griffiths JR, Ryan AJ, Blakey DC, Peers IS, Waterton JC (2004) Single dose of the antivascular agent, ZD6126 (N-acetylcolchinol-O-phosphate), reduces perfusion for at least 96 hours in the GH3 prolactinoma rat tumor model. Neoplasia 6:150–157CrossRefPubMedGoogle Scholar
  27. 27.
    Vogel-Claussen J, Gimi B, Artemov D, Bhujwalla ZM (2007) Diffusion-weighted and macromolecular contrast enhanced MRI of tumor response to antivascular therapy with ZD6126. Cancer Biol Ther 6:1469–1475CrossRefPubMedGoogle Scholar
  28. 28.
    Bradley DP, Tessier JJ, Ashton SE, Waterton JC, Wilson Z, Worthington PL, Ryan AJ (2007) Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats. Neoplasia 9:382–391CrossRefPubMedGoogle Scholar
  29. 29.
    Davis PD, Dougherty GJ, Blakey DC, Galbraith SM, Tozer GM, Holder AL, Naylor MA, Nolan J, Stratford MRL, Chaplin DJ, Hill SA (2002) ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature. Cancer Res 62:7247–7253PubMedGoogle Scholar
  30. 30.
    Blakey DC, Westwood FR, Walker M, Hughes GD, Davis PD, Ashton SE, Ryan AJ (2002) Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. Clin Cancer Res 8:1974–1983PubMedGoogle Scholar
  31. 31.
    Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MR, Dennis MF, Chaplin DJ (1999) Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res 59:1626–1634PubMedGoogle Scholar
  32. 32.
    Boucher Y, Baxter LT, Jain RK (1990) Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50:4478–4484PubMedGoogle Scholar
  33. 33.
    Horsman MR, Murata R (2003) Vascular targeting effects of ZD6126 in a C3H mouse mammary carcinoma and the enhancement of radiation response. Int J Radiat Oncol Biol Phys 57:1047–1055PubMedGoogle Scholar
  34. 34.
    Jaffer S, Bleiweiss IJ (2004) Beyond hematoxylin and eosin—the role of immunohistochemistry in surgical pathology. Cancer Invest 22:445–465CrossRefPubMedGoogle Scholar
  35. 35.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  36. 36.
    Lang P, Wendland MF, Saeed M, Gindele A, Rosenau W, Mathur A, Gooding CA, Genant HK (1998) Osteogenic sarcoma: noninvasive in vivo assessment of tumor necrosis with diffusion-weighted MR imaging. Radiology 206:227–235PubMedGoogle Scholar
  37. 37.
    Koh DM, Padhani AR (2006) Diffusion-weighted MRI: a new functional clinical technique for tumour imaging. Br J Radiol 79:633–635CrossRefPubMedGoogle Scholar
  38. 38.
    Collins DJ, Padhani AR (2004) Dynamic magnetic resonance imaging of tumor perfusion. Approaches and biomedical challenges. IEEE Eng Med Biol Mag 23:65–83CrossRefPubMedGoogle Scholar
  39. 39.
    Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, Jayson GC, Judson IR, Knopp MV, Maxwell RJ, McIntyre D, Padhani AR, Price P, Rathbone R, Rustin GJ, Tofts PS, Tozer GM, Vennart W, Waterton JC, Williams SR, Workman P (2005) The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 92:1599–1610CrossRefPubMedGoogle Scholar
  40. 40.
    Koh D-M, Collins DJ (2007) Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 188:1622–1635CrossRefPubMedGoogle Scholar
  41. 41.
    Deng J, Rhee TK, Sato KT, Salem R, Haines K, Paunesku T, Mulcahy MF, Miller FH, Omary RA, Larson AC (2006) In vivo diffusion-weighted imaging of liver tumor necrosis in the VX2 rabbit model at 1.5 Tesla. Invest Radiol 41:410–414CrossRefPubMedGoogle Scholar
  42. 42.
    Chen G, Horsman MR, Pedersen M, Pang Q, Stødkilde-Jørgensen H (2008) The effect of combretastatin A4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on water diffusion and blood perfusion in tumours. Acta Oncol 47:1071–1076CrossRefPubMedGoogle Scholar
  43. 43.
    Cui Y, Zhang X-P, Sun Y-S, Tang L, Shen L (2008) Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. Radiology 248:894–900CrossRefPubMedGoogle Scholar
  44. 44.
    Le Bihan D, Breton E, Lallemand D, Aubin ML, Vignaud J, Laval-Jeantet M (1988) Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 168:497–505PubMedGoogle Scholar
  45. 45.
    Avril N, Propper D (2007) Functional PET imaging in cancer drug development. Future Oncol 3:215–228CrossRefPubMedGoogle Scholar
  46. 46.
    Kelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, Link JM, Guyton KZ, Eckelman WC, Scher HI, O’Shaughnessy J, Cheson BD, Sigman CC, Tatum JL, Mills GQ, Sullivan DC, Woodcock J (2005) The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 11:7967–7985CrossRefPubMedGoogle Scholar
  47. 47.
    Schor-Bardach R, Alsop DC, Pedrosa I, Solazzo SA, Wang X, Marquis RP, Atkins MB, Regan M, Signoretti S, Lenkinski RE, Goldberg SN (2009) Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model? Radiology 251:731–742CrossRefPubMedGoogle Scholar

Copyright information

© European Society of Radiology 2010

Authors and Affiliations

  • Huaijun Wang
    • 1
  • Junjie Li
    • 1
  • Feng Chen
    • 1
    • 2
  • Frederik De Keyzer
    • 1
  • Jie Yu
    • 1
  • Yuanbo Feng
    • 1
  • Johan Nuyts
    • 3
  • Guy Marchal
    • 1
  • Yicheng Ni
    • 1
  1. 1.Department of RadiologyUniversity Hospitals, University of LeuvenLeuvenBelgium
  2. 2.Department of Radiology, Zhongda HospitalSoutheast UniversityNanjingChina
  3. 3.Department of Nuclear MedicineUniversity Hospitals, University of LeuvenLeuvenBelgium

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