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European Radiology
Published in: European Radiology 4/2015

01-04-2015 | Experimental

Magnetic resonance-imaging of the effect of targeted antiangiogenic gene delivery in a melanoma tumour model

Authors: Walter Hundt, Silke Steinbach, Dirk Mayer, Mykhaylo Burbelko, Andreas Kiessling, Jens Figiel, Samira Guccione

Published in: European Radiology | Issue 4/2015

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Abstract

Objectives

We investigated the effect of targeted gene therapy to melanoma tumours (M21) by MR-imaging.

Methods

M21 and M21-L tumours were grown to a size of 850 mm3. M21 and M21-L tumours were intravenously treated with an αvβ3-integrin-ligand-coupled nanoparticle (RGDNP)/RAF(-) complex five times every 72 hours. MRI was performed at set time intervals 24h and 72h after the i.v. injection of the complex. The MRI protocol was T1-wt-SE±CM, T2-wt-FSE, DCE-MRI, Diffusion-wt-STEAM-sequence, T2-time obtained on a 1.5-T-GE-MRI device.

Results

The size of the treated M21 tumours kept nearly constant during the treatment phase (847.8±31.4 mm3 versus 904.8±44.4 mm3). The SNR value (T2-weighted images) of the tumours was 36.7±0.6 and dropped down to 30.6±1.9 (p=0.004). At the beginning the SNR value (T1-weighted images) of the tumours after contrast medium application was 42.3±1.9 and dropped down to 28.5±3.0 (p<0.001). In the treatment group the diffusion coefficient increased significantly under therapy (0.54±0.01x10-3 mm2/s versus 0.67±0.04x10-3 mm2/s). The DCE-MRI showed a reduction of the slope and of the Akep of 67.8±4.3 % respectively 64.8±3.3 % compared to baseline.

Conclusions

Targeted gene delivery therapy induces significant changes in MR-imaging. MRI showed a significant reduction of contrast medium uptake parameters and increase of the diffusion coefficient of the tumours.

Key point

• Treatment with targeted gene-delivery therapy can be monitored by MR imaging
• DCE and diffusion-weighted imaging are appropriate methods for monitoring this therapy
• Functional changes are significant prior to any morphological changes
Literature
1.
van der Schaft DWJ, Ramkrishnan S, Molema G, Griffioen AW in: G. Molema, D.K.F. Meijer (eds),(2001) Drug Targeting: Organ-Specific Strategies, Wiley-VCH, Weinheim M 233–254
2.
Fukumura D, Duda DG, Munn LL, Jain RK (2010) Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 17(3):206–25CrossRefPubMedCentralPubMed
3.
Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct av integrins. Science 270:1500–1502CrossRefPubMed
4.
Hammes HP, Brownlee M, Jonczyk A, Sutter A, Preissner KT (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularisation. Nat Med 2:529–533CrossRefPubMed
5.
Erdreich-Epstein A, Shimada H, Groshen S, Liu M, Metelitsa LS, Kim KS, Stins MF, Seeger RC, Durden DL (2000) Integrins avß3 and avß5 are expressed by endothelium of high-risk neuroblastoma and their inhibition is associated with increased endogenous ceramide. Cancer Res 60:712–721PubMed
6.
Baeten CI, Hillen F, Pauwels P, de Bruine AP, Baeten CG (2009) Prognostic role of vasculogenic mimicry in colorectal cancer. Dis Colon Rectum 52(12):2028–35CrossRefPubMed
7.
Blezinger P, Wang J, Gondo M, Quezada A, Mehrens D, French M, Singhal A, Sullivan S, Rolland A, Ralston R, Min W (1999) Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. Nat Biotechnol 17(4):343–348CrossRefPubMed
8.
Wang Y, Becker D (1997) Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 3(8):887–893CrossRefPubMed
9.
Takeshita S, Tsurumi Y, Couffinahl T, Asahara T, Bauters C, Symes J, Ferrara N, Isner JM (1996) Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest 75(4):487–501PubMed
10.
Berinstein A, Roivainen M, Hovi T, Mason PW, Baxt B (1995) Antibodies to the vitronectin receptor (integrin alpha V beta 3) inhibit binding and infection of foot-and-mouth disease virus to cultured cells. J Virol 69(4):2664–2666PubMedCentralPubMed
11.
Guerrero CA, Méndez E, Zárate S, Isa P, López S, Arias CF (2000) Integrin alpha(v)beta(3) mediates rotavirus cell entry. Proc Natl Acad Sci U S A 97(26):14644–14649CrossRefPubMedCentralPubMed
12.
Wickham TJ, Mathias P, Cheresh DA, Nemerow GR (1993) Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 1993:309–319CrossRef
13.
Hood J, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh D (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 2404–2407
14.
Mayr NA, Yuh WT, Magnotta VA, Ehrhardt JC, Wheeler JA, Sorosky JI, Davis CS, Wen BC, Martin DD, Pelsang RE, Buller RE, Oberley LW, Mellenberg DE, Hussey DH (1993) Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay. Int J Radiat Oncol Biol Phys 6(3):623–633
15.
Hawighorst H, Knapstein PG, Weikel W, Knopp MV, Zuna I, Knof A, Brix G, Schaeffer U, Wilkens C, Schoenberg SO, Essig M, Vaupel P, van Kaick G (1997) Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement. Cancer Res 57(21):4777–86PubMed
16.
Huber P, Jenne J, Rastert R, Simiantonakis I, Sinn HP, Strittmatter HJ, Fournier D, Wannenmacher M, Debus J (2001) A New Noninvasive Approach in Breast Cancer Therapy Using Magnetic Resonance Imaging-guided Focused Ultrasound Surgery. Cancer Res 61:8441–8447PubMed
17.
Kloeckner R, Otto G, Biesterfeld S, Oberholzer K, Dueber C, Pitton MB (2010) MDCT versus MRI assessment of tumor response after transarterial chemoembolization for the treatment of hepatocellular carcinoma. Cardiovasc Intervent Radiol 33(3):532–540CrossRefPubMed
18.
Akisik MF, Sandrasegaran K, Bu G, Lin C, Hutchins GD, Chiorean EG (2010) Pancreatic Cancer: Utility of Dynamic Contrast-enhanced MR Imaging in Assessment of Antiangiogenic Therapy. Radiology 256(2):441–449CrossRefPubMed
19.
Farrar CT, Kamoun WS, Ley CD, Kim YR, Kwon SJ, Dai G, Rosen BR, di Tomaso E, Jain RK, Sorensen AG (2010) In vivo validation of MRI vessel caliber index measurement methods with intravital optical microscopy in a U87 mouse brain tumor model. Neuro Oncol 12(4):341–350CrossRefPubMedCentralPubMed
20.
Colagrande S, Carbone SF, Carusi LM, Cova M, Villari N (2006) Magnetic resonance diffusion-weighted imaging: extraneurological applications. Radiol Med 111(3):392–419CrossRefPubMed
21.
Mannelli L, Kim S, Hajdu CH, Babb JS, Clark TW, Taouli B (2009) Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver. Am J Roentgenol 193(4):1044–10521CrossRef
22.
23.
Zhu W, Kato Y (2014) Artemov D (2014) Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI. PLoS One 9(1):e8658CrossRef
24.
Felding-Habermann B, Mueller M, Romerdahl CA, Cheresh DA (1992) Involement of integrin alpha V gene expression in human melanom tumorigenicity. J Clin Investig 89:2018CrossRefPubMedCentralPubMed
25.
Tropper FD, Li HY, Song CK, Sipkins DA, Kuniyoshi JK, Bednarski MD, Strauss HW, Li KC (1995) Paramagnetic polymerized liposomes as new recirculating MR contrast agents. J Magn Reson Imaging 5(6):719–724CrossRefPubMed
26.
Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KC (1998) Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. Nat Med 4(5):623–626CrossRefPubMed
27.
Hoffmann U, Brix G, Knopp MV, Hess T, Lorenz WJ (1995) Pharmacokinetic mapping of the breast: a new method for dynamic MR mammography. Magn Reson Med 33:506–514CrossRefPubMed
28.
Brix G, Semmler W, Port R, Schad LR, Layer G, Lorenz WJ (1991) Pharmacokinetic parameters in CNS Gd-DTPA enhanced MR imaging. J Comput Assist Tomogr 15:621–628CrossRefPubMed
29.
Gutheil JC, Campbell TN, Pierce PR et al (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 6:3056–3061PubMed
30.
Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal cell carcinoma. N Engl J Med 356:125–134CrossRefPubMed
31.
Cyran CC, Schwarz B, Paprottka PM, Sourbron S, von Einem JC, Dietrich O, Hinkel R, Clevert DA, Bruns CJ, Reiser MF, Nikolaou K, Wintersperger BJ (2013) In vivo monitoring of sorafenib therapy effects on experimental prostate carcinomas using dynamic contrast-enhanced MRI and macromolecular contrast media. Cancer Imaging 13(4):557–66CrossRefPubMedCentralPubMed
32.
Sieghart W, Pinter M, Reisegger M, Müller C, Ba-Ssalamah A, Lammer J, Peck-Radosavljevic M (2012) Conventional transarterial chemoembolisation in combination with sorafenib for patients with hepatocellular carcinoma: a pilot study. Eur Radiol 22(6):1214–23CrossRefPubMed
33.
Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434CrossRefPubMedCentralPubMed
34.
Bex A, Fournier L, Lassau N, Mulders P, Nathan P, Oyen WJ, Powles T (2014) Assessing the Response to Targeted Therapies in Renal Cell Carcinoma Technical Insights and Practical Considerations. Eur Urol 65(4):766–777CrossRefPubMed
35.
Hüser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S, Sun XM, Brown J, Marais R, Pritchard C (2001) MEK kinase activity is not necessary for Raf-1 function. EMBO J 20(8):1940–1951CrossRefPubMedCentralPubMed
36.
Tuncbilek N, Kaplan M, Altaner S et al (2009) Value of dynamic contrast-enhanced MRI and correlation with tumor angiogenesis in bladder cancer. AJR 192:949–955CrossRefPubMed
37.
Mulder WJ, Strijkers GJ, Habets JW, Bleeker EJ, van der Schaft DW, Storm G, Koning GA, Griffioen AW, Nicolay K (2005) MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle. FASEB J 19:2008–2010PubMed
38.
Mulder WJM, van der Schaft DWJ, Hautvast PAI et al (2007) Early in vivo assessment of angiostatic therapy efficacy by molecular MRI. FASEB J 21:378–383CrossRefPubMed
39.
Liu G, Rugo HS, Wilding G et al (2005) Dynamic contrastenhanced 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 23:5464–5473CrossRefPubMed
40.
Hyodo F, Chandramouli GV, Matsumoto S, Matsumoto K, Mitchell JB, Krishna MC, Munasinghe JP (2009) Estimation of tumor microvessel density by MRI using a blood pool contrast agent. Int J Oncol 35(4):797–804PubMed
41.
Ungersma SE, Pacheco G, Ho C, Yee SF, Ross J, van Bruggen N, Peale FV Jr, Ross S, Carano RA (2010) Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis. Magn Reson Med Jun 63(6):1637–47CrossRef
42.
Lyng H, Haraldseth O, Rofstad EK (2000) Measurement of cell density and necrotic fraction in human melanoma xenografts by diffusion weighted magnetic resonance imaging. Magn Reson Med 43:823–836CrossRef
43.
Chenevert TL, Ross BD (2009) Diffusion imaging for therapy response assessment of brain tumor. Neuroimaging Clin N Am 19(4):559–571
44.
Chung JC, Naik NK, Lewandowski RJ, Deng J, Mulcahy MF, Kulik LM, Sato KT, Ryu RK, Salem R, Larson AC, Omary RA (2010) Diffusion-weighted magnetic resonance imaging to predict response of hepatocellular carcinoma to chemoembolization. World J Gastroenterol 16(25):3161–3167
45.
Hamstra DA, Rehemtulla A, Ross BD (2007) Diffusion magnetic resonance imaging: a biomarker for treatment response in oncology. J Clin Oncol 25(26):4104–4109
46.
Rehemtulla A, Hall DE, Stegmanet LD et al (2002) Molecular imaging of gene expression and efficacy following adenoviral-mediated brain tumor gene therapy. Molec Imaging 1:43–55
Metadata
Title
Magnetic resonance-imaging of the effect of targeted antiangiogenic gene delivery in a melanoma tumour model
Authors
Walter Hundt
Silke Steinbach
Dirk Mayer
Mykhaylo Burbelko
Andreas Kiessling
Jens Figiel
Samira Guccione
Publication date
01-04-2015
Publisher
Springer Berlin Heidelberg
Published in
European Radiology / Issue 4/2015
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-014-3492-3

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