Gadofosveset‑enhanced MRI as simple surrogate parameter for real‑time evaluation of the initial tumour vessel infarction by retargeted tissue factor tTF‑NGR

Höink,Anna; Persigehl,Thorsten; Kwiecien,Robert; Balthasar,Martin; Mesters,Rolf; Berdel,Wolfgang; Heindel,Walter; Bremer,Christoph; Schwöppe,Christian

doi:10.3892/ol.2018.9638

Gadofosveset‑enhanced MRI as simple surrogate parameter for real‑time evaluation of the initial tumour vessel infarction by retargeted tissue factor tTF‑NGR

Authors:
- Anna Höink
- Thorsten Persigehl
- Robert Kwiecien
- Martin Balthasar
- Rolf Mesters
- Wolfgang Berdel
- Walter Heindel
- Christoph Bremer
- Christian Schwöppe
View Affiliations

Affiliations: Department of Clinical Radiology, University Hospital Münster, D‑48149 Münster, Germany, Institute of Biostatistics and Clinical Research, University of Münster, D‑48149 Münster, Germany, Department of Diagnostic and Interventional Radiology, University Hospital Cologne, D‑50937 Cologne, Germany, Department of Medicine A ‑ Haematology and Oncology, University Hospital Münster, D‑48149 Münster, Germany, Department of Radiology, St. Franziskus‑Hospital Münster, D‑48145 Münster, Germany
Published online on: October 29, 2018 https://doi.org/10.3892/ol.2018.9638
Pages: 270-280
Copyright: © Höink et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Truncated tissue factor (tTF)‑NGR consists of the extracellular domain of the human TF and the binding motif NGR. tTF‑NGR activates blood coagulation within the tumour vasculature following binding to CD13, and is overexpressed in the endothelial cells of tumour vessels, resulting in tumour vessel infarction and subsequent retardation/regression of tumour growth. The aim of the present study was to investigate gadofosveset‑based real‑time dynamic contrast-enhanced magnetic resonance imaging (DCE‑MRI) in evaluating the initial therapeutic effects of the anti‑vascular tTF‑NGR approach. DCE‑MRI (3.0 T) was performed in human U87‑glioblastoma tumour‑bearing nude mice. During a dynamic T1w GE‑sequence, a gadolinium‑based blood pool contrast agent (gadofosveset) was injected via a tail vein catheter. Following the maximum contrast intensity inside the tumour being obtained, tTF‑NGR was injected (controls received NaCl) and the contrast behaviour of the tumour was monitored by ROI analysis. The slope difference of signal intensities between controls and the tTF‑NGR group was investigated, as well as the differences between the average area under the curve (AUC) of the two groups. The association between intensity, group (control vs. tTF‑NGR group) and time was analysed by fitting a linear mixed model. Following the injection of tTF‑NGR, the signal intensity inside the tumours exhibited a statistically significantly stronger average slope decrease compared with the signal intensity of the tumours in the NaCl group. Furthermore, the initial average AUC values of mice treated with tTF‑NGR were 5.7% lower than the average AUC of the control animals (P<0.05). Gadofosveset‑enhanced MRI enables the visualization of the initial tumour response to anti‑vascular treatment in real‑time. Considering the clinical application of tTF‑NGR, this method may provide a simple alternative parameter for monitoring the tumour response to vascular disrupting agents and certain vascular targeting agents in humans.

View Figures

View References

1	Gwyther SJ and Schwartz LH: How to assess anti-tumour efficacy by imaging techniques. Eur J Cancer. 44:39–45. 2008. View Article : Google Scholar : PubMed/NCBI
2	Contractor KB and Aboagye EO: Monitoring predominantly cytostatic treatment response with 18F-FDG PET. J Nucl Med. 50 Suppl 1:97S–105S. 2009. View Article : Google Scholar : PubMed/NCBI
3	de Bazelaire C, Alsop DC, George D, Pedrosa I, Wang Y, Michaelson MD and Rofsky NM: Magnetic resonance imaging-measured blood flow change after antiangiogenic therapy with PTK787/ZK 222584 correlates with clinical outcome in metastatic renal cell carcinoma. Clin Cancer Res. 14:5548–5554. 2008. View Article : Google Scholar : PubMed/NCBI
4	Padhani AR, Krohn KA, Lewis JS and Alber M: Imaging oxygenation of human tumours. Eur Radiol. 17:861–872. 2007. View Article : Google Scholar : PubMed/NCBI
5	Carmetliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med. 6:389–395. 2000. View Article : Google Scholar : PubMed/NCBI
6	Kerbel RS: Antiangiogenic therapy: A universal chemosensitization strategy for cancer? Science. 312:1171–1175. 2006. View Article : Google Scholar : PubMed/NCBI
7	Murphy DA, Makonnen S, Lassoued W, Feldman MD, Carter C and Lee WM: Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am J Pathol. 169:1875–1885. 2006. View Article : Google Scholar : PubMed/NCBI
8	Thorpe PE: Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 10:415–427. 2004. View Article : Google Scholar : PubMed/NCBI
9	Kessler T, Schwöppe C, Liersch R, Schliemann C, Hintelmann H, Bieker R, Berdel WE and Mesters RM: Generation of fusion proteins for selective occlusion of tumor vessels. Curr Drug Discov Technol. 5:1–8. 2008. View Article : Google Scholar : PubMed/NCBI
10	Samad F and Ruf W: Inflammation, obesity, and thrombosis. Blood. 122:3415–3422. 2013. View Article : Google Scholar : PubMed/NCBI
11	Eisenreich A: Regulation of vascular function on posttranscriptional level. Thrombosis. 2013:9487652013. View Article : Google Scholar : PubMed/NCBI
12	Bieker R, Kessler T, Schwöppe C, Padró T, Persigehl T, Bremer C, Dreischalück J, Kolkmeyer A, Heindel W, Mesters RM and Berdel WE: Infarction of tumor vessels by NGR-peptide directed targeting of tissue factor. Experimental results and first-in-man experience. Blood. 113:5019–5027. 2009. View Article : Google Scholar : PubMed/NCBI
13	Nilsson F, Kosmehl H, Zardi L and Neri D: Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res. 61:711–716. 2001.PubMed/NCBI
14	Liu C, Huang H and Doñate F: Prostate-specific membrane antigen directed selective thrombotic infarction of tumors. Cancer Res. 62:5470–5475. 2002.PubMed/NCBI
15	Hu P, Yan J, Sharifi J, Bai T, Khawli LA and Epstein AL: Comparison of three different targeted tissue factor fusion proteins for inducing tumor vessel thrombosis. Cancer Res. 63:5046–5053. 2003.PubMed/NCBI
16	Schwöppe C, Kessler T, Persigehl T, Liersch R, Hintelmann H, Dreischalück J, Ring J, Bremer C, Heindel W, Mesters RM and Berdel WE: Tissue-factor proteins induce occlusion of tumor vessels. Thromb Res. 125 Suppl 2:S143–S150. 2010. View Article : Google Scholar : PubMed/NCBI
17	Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A, Ashmun RA, Shapiro LH, Arap W and Ruoslahti E: Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res. 60:722–727. 2000.PubMed/NCBI
18	Kessler T, Bieker R, Padró T, Schwöppe C, Persigehl T, Bremer C, Kreuter M, Berdel WE and Mesters RM: Inhibition of tumor growth by RGD peptide-directed delivery of truncated tissue factor to the tumor vasculature. Clin Cancer Res. 11:6317–6324. 2005. View Article : Google Scholar : PubMed/NCBI
19	Persigehl T, Ring J, Bremer C, Heindel W, Holtmeier R, Stypmann J, Claesener M, Hermann S, Schäfers M, Zerbst C, et al: Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF-NGR using multi-modal imaging. Angiogenesis. 17:235–246. 2014. View Article : Google Scholar : PubMed/NCBI
20	Persigehl T, Matuszewski L, Kessler T, Wall A, Meier N, Ebert W, Berdel WE, Heindel W, Mesters R and Bremer C: Prediction of antiangiogenic treatment efficacy by iron oxide enhanced parametric magnetic resonance imaging. Invest Radiol. 42:791–796. 2007. View Article : Google Scholar : PubMed/NCBI
21	Sabach AS, Bruno M, Kim D, Mulholland T, Lee L, Kaura S and Lim RP: Gadofosveset trisodium: Abdominal and peripheral vascular applications. AJR Am J Roentgenol. 200:1378–1386. 2013. View Article : Google Scholar : PubMed/NCBI
22	Allen M, Bjerke M, Edlund H, Nelander S and Westermark B: Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med. 8:354re32016. View Article : Google Scholar : PubMed/NCBI
23	Schwöppe C, Zerbst C, Fröhlich M, Schliemann C, Kessler T, Liersch R, Overkamp L, Holtmeier R, Stypmann J, Dreiling A, et al: Anticancer therapy by tumor vessel infarction with polyethylene glycol conjugated retargeted tissue factor. J Med Chem. 56:2337–2347. 2013. View Article : Google Scholar : PubMed/NCBI
24	Persigehl T, Bieker R, Matuszewski L, Wall A, Kessler T, Kooijman H, Meier N, Ebert W, Berdel WE, Heindel W, et al: Antiangiogenic tumor treatment: Early noninvasive monitoring with USPIO-enhanced MR imaging in mice. Radiology. 244:449–456. 2007. View Article : Google Scholar : PubMed/NCBI
25	Stucke-Ring J, Ronnacker J, Brand C, Höltke C, Schliemann C, Kessler T, Schmidt LH, Harrach S, Mantke V, Hintelmann H, et al: Combinatorial effects of doxorubicin and retargeted tissue factor tTF-NGR by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction. Oncotarget. 7:82458–82472. 2016. View Article : Google Scholar : PubMed/NCBI
26	Höink AJ, Heindel W and Buerke B: Radiological evaluation of the therapeutic response of malignant diseases: Status quo, innovative developments and requirements for radiology. Rofo. 186:927–936. 2014. View Article : Google Scholar : PubMed/NCBI
27	Zweifel M and Padhani AR: Perfusion MRI in the early clinical development of antivascular drugs: Decorations or decision making tools? Eur J Nucl Med Mol Imaging. 37 (Suppl 1):S164–S182. 2010. View Article : Google Scholar : PubMed/NCBI
28	Salmon BA, Salmon HW and Siemann DW: Monitoring the treatment efficacy of the vascular disrupting agent CA4P. Eur J Cancer. 43:1622–1629. 2007. View Article : Google Scholar : PubMed/NCBI
29	Kim KW, Lee JM, Jeon YS, Lee IJ, Choi Y, Park J, Kiefer B, Kim C, Han JK and Choi BI: Vascular disrupting effect of CKD-516: Preclinical study using DCE-MRI. Invest New Drugs. 31:1097–1106. 2013. View Article : Google Scholar : PubMed/NCBI
30	European Medicines Agency: EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/07/news_detail_002780.jsp&mid=WC0b01ac058004d5c1Jul. 21. 2017
31	Rezai P, Pisaneschi MJ, Feng C and Yaghmai V: A radiologist's guide to treatment response criteria in oncologic imaging: Functional, molecular, and disease-specific imaging biomarkers. AJR Am J Roentgenol. 201:246–256. 2013. View Article : Google Scholar : PubMed/NCBI
32	Thoeny HC and Ross BD: Predicting and monitoring cancer treatment response with diffusion-weighted MRI. J Magn Reson Imaging. 32:2–16. 2010. View Article : Google Scholar : PubMed/NCBI