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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

[18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice

Authors: Mette Munk Jensen, Kamille Dumong Erichsen, Camilla Bardram Johnbeck, Fredrik Björkling, Jacob Madsen, Peter Buhl Jensen, Maxwell Sehested, Liselotte Højgaard, Andreas Kjær

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models.

Methods

In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) were studied after treatment with belinostat. Mice were divided in 2 groups receiving either belinostat (40 mg/kg ip twice daily Day 0–4 and 6–10) or vehicle. Baseline [18F]FLT or [18F]FDG scans were made before treatment (Day 0) and repeated at Day 3, 6 and 10. Tracer uptake was quantified using small animal PET/CT.

Results

Tumors in the belinostat group had volumes that were 462 ± 62% (640 mm3) at Day 10 relative to baseline which was significantly different (P = 0.011) from the control group 769 ± 74% (926 mm3). [18F]FLT SUVmax increased from baseline to Day 10 (+30 ± 9%; P = 0.048) in the control group. No increase was observed in the treatment group. [18F]FDG SUVmean was significantly different in the treatment group compared to the control group (P = 0.0023) at Day 10. Within treatment groups [18F]FDG uptake and to a lesser extent [18F]FLT uptake at Day 3 were significantly correlated with tumor growth at Day 10.

Conclusions

[18F]FDG uptake early following treatment initiation predicted tumor sizes at Day 10, suggesting that [18F]FDG may be a valuable biomarker for non-invasive assessment of anti-tumor activity of belinostat.
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Literature
1.
Arner ES, Eriksson S: Mammalian deoxyribonucleoside kinases. Pharmacol Ther. 1995, 67: 155-186. 10.1016/0163-7258(95)00015-9.CrossRefPubMed
2.
Barthel H, Perumal M, Latigo J, He Q, Brady F, Luthra SK: The uptake of 3'-deoxy-3'-[18 F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging. 2005, 32: 257-263. 10.1007/s00259-004-1611-0.CrossRefPubMed
3.
Kong XB, Zhu QY, Vidal PM, Watanabe KA, Polsky B, Armstrong D: Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine. Antimicrob Agents Chemother. 1992, 36: 808-818. 10.1128/AAC.36.4.808.CrossRefPubMedPubMedCentral
4.
Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL: Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002, 43: 1210-1217.PubMed
5.
Sherley JL, Kelly TJ: Regulation of human thymidine kinase during the cell cycle. J Biol Chem. 1988, 263: 8350-8358.PubMed
6.
Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM: Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998, 4: 1334-1336. 10.1038/3337.CrossRefPubMed
7.
Apisarnthanarax S, Alauddin MM, Mourtada F, Ariga H, Raju U, Mawlawi O: Early detection of chemoradioresponse in esophageal carcinoma by 3'-deoxy-3'-3H-fluorothymidine using preclinical tumor models. Clin Canc Res. 2006, 12: 4590-4597. 10.1158/1078-0432.CCR-05-2720.CrossRef
8.
Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q: 3'-deoxy-3'-[18 F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Canc Res. 2003, 63: 3791-3798.
9.
Brepoels L, Stroobants S, Verhoef G, De GT, Mortelmans L, De Wolf-Peeters C: 18 F-FDG and 18 F-FLT Uptake Early After Cyclophosphamide and mTOR Inhibition in an Experimental Lymphoma Model. J Nucl Med. 2009, 50: 1102-1109. 10.2967/jnumed.109.062208.CrossRefPubMed
10.
Leyton J, Latigo JR, Perumal M, Dhaliwal H, He Q, Aboagye EO: Early detection of tumor response to chemotherapy by 3'-deoxy-3'-[18 F]fluorothymidine positron emission tomography: the effect of cisplatin on a fibrosarcoma tumor model in vivo. Canc Res. 2005, 65: 4202-4210. 10.1158/0008-5472.CAN-04-4008.CrossRef
11.
Leyton J, Alao JP, Da CM, Stavropoulou AV, Latigo JR, Perumal M: In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18 F]fluorothymidine positron emission tomography. Canc Res. 2006, 66: 7621-7629. 10.1158/0008-5472.CAN-05-3962.CrossRef
12.
Manning HC, Merchant NB, Foutch AC, Virostko JM, Wyatt SK, Shah C: Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer. Clin Canc Res. 2008, 14: 7413-7422. 10.1158/1078-0432.CCR-08-0239.CrossRef
13.
Molthoff CF, Klabbers BM, Berkhof J, Felten JT, van Gelder M, Windhorst AD: Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice: comparison of 2'-deoxy-2'-[18 F]fluoro-D-glucose (FDG) and 3'-[18 F]fluoro-3'-deoxythymidine (FLT). Mol Imaging Biol. 2007, 9: 340-347. 10.1007/s11307-007-0104-5.CrossRefPubMedPubMedCentral
14.
Oyama N, Ponde DE, Dence C, Kim J, Tai YC, Welch MJ: Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation. J Nucl Med. 2004, 45: 519-525.PubMed
15.
Shah C, Miller TW, Wyatt SK, McKinley ET, Olivares MG, Sanchez V: Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. Clin Canc Res. 2009, 15: 4712-4721. 10.1158/1078-0432.CCR-08-2635.CrossRef
16.
Waldherr C, Mellinghoff IK, Tran C, Halpern BS, Rozengurt N, Safaei A: Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18 F-fluorothymidine PET. J Nucl Med. 2005, 46: 114-120.PubMed
17.
Yang YJ, Ryu JS, Kim SY, Oh SJ, Im KC, Lee H: Use of 3'-deoxy-3'-[18 F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors. Eur J Nucl Med Mol Imaging. 2006, 33: 412-419. 10.1007/s00259-005-0011-4.CrossRefPubMed
18.
Buck AK, Schirrmeister H, Hetzel M, Von Der HM, Halter G, Glatting G: 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Canc Res. 2002, 62: 3331-3334.
19.
Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P: In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Canc Res. 2002, 8: 3315-3323.
20.
Yamamoto Y, Nishiyama Y, Ishikawa S, Nakano J, Chang SS, Bandoh S: Correlation of 18 F-FLT and 18 F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2007, 34: 1610-1616. 10.1007/s00259-007-0449-7.CrossRefPubMed
21.
Weber WA, Wieder H: Monitoring chemotherapy and radiotherapy of solid tumors. Eur J Nucl Med Mol Imaging. 2006, 33 (Suppl 1): 27-37.CrossRefPubMed
22.
23.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Canc. 2009, 45: 228-247. 10.1016/j.ejca.2008.10.026.CrossRef
24.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L: 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 Canc Inst. 2000, 92: 205-216. 10.1093/jnci/92.3.205.CrossRef
25.
Wahl RL, Jacene H, Kasamon Y, Lodge MA: From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med. 2009, 50 (Suppl 1): 122S-150S.CrossRefPubMedPubMedCentral
26.
Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ: Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Canc Ther. 2003, 2: 721-728.
27.
Qian X, LaRochelle WJ, Ara G, Wu F, Petersen KD, Thougaard A: Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Canc Ther. 2006, 5: 2086-2095. 10.1158/1535-7163.MCT-06-0111.CrossRef
28.
Tumber A, Collins LS, Petersen KD, Thougaard A, Christiansen SJ, Dejligbjerg M: The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Canc Chemother Pharmacol. 2007, 60: 275-283. 10.1007/s00280-006-0374-7.CrossRef
29.
Qian X, Ara G, Mills E, LaRochelle WJ, Lichenstein HS, Jeffers M: Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Canc. 2008, 122: 1400-1410.CrossRef
30.
Monks A, Hose CD, Pezzoli P, Kondapaka S, Vansant G, Petersen KD: Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009, 20: 682-692. 10.1097/CAD.0b013e32832e14e1.CrossRefPubMed
31.
Gravina GL, Marampon F, Giusti I, Carosa E, Di SS, Ricevuto E: Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models. Int J Oncol. 2012, 40: 711-720.PubMed
32.
Ozols RF, Bookman MA, Connolly DC, Daly MB, Godwin AK, Schilder RJ: Focus on epithelial ovarian cancer. Canc Cell. 2004, 5: 19-24. 10.1016/S1535-6108(04)00002-9.CrossRef
33.
Molife LR, de Bono JS: Belinostat: clinical applications in solid tumors and lymphoma. Expert Opin Investig Drugs. 2011, 20: 1723-1732. 10.1517/13543784.2011.629604.CrossRefPubMed
34.
Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE: A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol. 2008, 81: 170-176. 10.1111/j.1600-0609.2008.01102.x.CrossRefPubMed
35.
Lassen U, Molife LR, Sorensen M, Engelholm SA, Vidal L, Sinha R: A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours. Br J Canc. 2010, 103: 12-17. 10.1038/sj.bjc.6605726.CrossRef
36.
Steele NL, Plumb JA, Vidal L, Tjornelund J, Knoblauch P, Rasmussen A: A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Canc Res. 2008, 14: 804-810. 10.1158/1078-0432.CCR-07-1786.CrossRef
37.
Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P: Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Canc. 2010, 46: 1573-1579. 10.1016/j.ejca.2010.02.047.CrossRef
38.
Dizon DS, Blessing JA, Penson RT, Drake RD, Walker JL, Johnston CM: A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2012, 125: 367-371. 10.1016/j.ygyno.2012.02.019.CrossRefPubMedPubMedCentral
39.
Dizon DS, Damstrup L, Finkler NJ, Lassen U, Celano P, Glasspool R: Phase II Activity of Belinostat (PXD-101), Carboplatin, and Paclitaxel in Women With Previously Treated Ovarian Cancer. Int J Gynecol Canc. 2012, 22: 979-986. 10.1097/IGC.0b013e31825736fd.CrossRef
40.
Stimson L, La Thangue NB: Biomarkers for predicting clinical responses to HDAC inhibitors. Canc Lett. 2009, 280: 177-183. 10.1016/j.canlet.2009.03.016.CrossRef
41.
Jensen MM, Erichsen KD, Bjorkling F, Madsen J, Jensen PB, Hojgaard L: Early detection of response to experimental chemotherapeutic Top216 with [18 F]FLT and [18 F]FDG PET in human ovary cancer xenografts in mice. PLoS One. 2010, 5: e12965-10.1371/journal.pone.0012965.CrossRefPubMedPubMedCentral
42.
Jensen MM, Jorgensen JT, Binderup T, Kjaer A: Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. BMC Med Imaging. 2008, 8: 16-10.1186/1471-2342-8-16.CrossRefPubMedPubMedCentral
43.
Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D: Impact of animal handling on the results of 18 F-FDG PET studies in mice. J Nucl Med. 2006, 47: 999-1006.PubMed
44.
Hellemans J, Mortier G, De PA, Speleman F, Vandesompele J: qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 2007, 8: R19-10.1186/gb-2007-8-2-r19.CrossRefPubMedPubMedCentral
45.
Dokmanovic M, Marks PA: Prospects: histone deacetylase inhibitors. J Cell Biochem. 2005, 96: 293-304. 10.1002/jcb.20532.CrossRefPubMed
46.
Dittmann H, Dohmen BM, Kehlbach R, Bartusek G, Pritzkow M, Sarbia M: Early changes in [18 F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging. 2002, 29: 1462-1469. 10.1007/s00259-002-0925-z.CrossRefPubMed
47.
Plotnik DA, McLaughlin LJ, Krohn KA, Schwartz JL: The effects of 5-fluoruracil treatment on 3'-fluoro-3'-deoxythymidine (FLT) transport and metabolism in proliferating and non-proliferating cultures of human tumor cells. Nucl Med Biol. 2012, 39: 970-976. 10.1016/j.nucmedbio.2012.03.009.CrossRefPubMedPubMedCentral
48.
Na YS, Jung KA, Kim SM, Hong YS, Ryu MH, Jang SJ: The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models. Canc Chemother Pharmacol. 2011, 68: 389-398. 10.1007/s00280-010-1495-6.CrossRef
49.
Munk JM, Erichsen KD, Bjorkling F, Madsen J, Jensen PB, Sehested M: 18 F]FLT PET for non-invasive assessment of tumor sensitivity to chemotherapy: studies with experimental chemotherapy TP202377 in human cancer xenografts in mice. PLoS One. 2012, 7: e50618-10.1371/journal.pone.0050618.CrossRef
50.
Aide N, Kinross K, Cullinane C, Roselt P, Waldeck K, Neels O: 18 F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model. J Nucl Med. 2010, 51: 1559-1564. 10.2967/jnumed.109.073288.CrossRefPubMed
51.
Perumal M, Stronach EA, Gabra H, Aboagye EO: Evaluation of 2-deoxy-2-[18 F]fluoro-D-glucose- and 3'-deoxy-3'-[18 F]fluorothymidine-positron emission tomography as biomarkers of therapy response in platinum-resistant ovarian cancer. Mol Imaging Biol. 2012, 14: 753-761. 10.1007/s11307-012-0554-2.CrossRefPubMed
52.
Wardell SE, Ilkayeva OR, Wieman HL, Frigo DE, Rathmell JC, Newgard CB: Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol. 2009, 23: 388-401.CrossRefPubMed
53.
Hiyoshi Y, Watanabe M, Imamura Y, Nagai Y, Baba Y, Yoshida N: The relationship between the glucose transporter type 1 expression and F-fluorodeoxyglucose uptake in esophageal squamous cell carcinoma. Oncology. 2009, 76: 286-292. 10.1159/000207505.CrossRefPubMed
54.
Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T: Biologic correlation of 2-[18 F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol. 2010, 28: 3746-3753. 10.1200/JCO.2009.27.4662.CrossRefPubMed
55.
Tan PH, Bay BH, Yip G, Selvarajan S, Tan P, Wu J: Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death. Mod Pathol. 2005, 18: 374-381. 10.1038/modpathol.3800254.CrossRefPubMed
56.
Yamamoto S, Ibusuki M, Yamamoto Y, Fu P, Fujiwara S, Murakami K: Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens. Breast Canc. 2012, 10.1007/s12282-012-0332-7
Metadata
Title
[18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice
Authors
Mette Munk Jensen
Kamille Dumong Erichsen
Camilla Bardram Johnbeck
Fredrik Björkling
Jacob Madsen
Peter Buhl Jensen
Maxwell Sehested
Liselotte Højgaard
Andreas Kjær
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-168

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