nach oben

European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

01.04.2006 | Molecular imaging

Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033

verfasst von: Donna S. Dorow, Carleen Cullinane, Nelly Conus, Peter Roselt, David Binns, Timothy J. McCarthy, Grant A. McArthur, Rodney J. Hicks

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 4/2006

Einloggen, um Zugang zu erhalten

Abstract

Purpose

This study was designed as “proof of concept” for a drug development model utilising multi-tracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy.

Methods

Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6–8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [¹⁸F]fluorodeoxyglucose, [¹⁸F]fluoro-L-thymidine, [¹⁸F]fluoro-azoazomycinarabinoside or [¹⁸F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia.

Results

During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20–60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment.

Conclusion

CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response.

Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 2005;45:357–384PubMedCrossRef

Sawyers C. Targeted cancer therapy. Nature 2004;432:294–297PubMedCrossRef

Solomon B, McArthur G, Cullinane C, Zalcberg J, Hicks R. Applications of positron emission tomography in the development of molecular targeted cancer therapeutics. BioDrugs 2003;17:339–354PubMedCrossRef

Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel BA, Cheng EY, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 2005;11:2785–2808PubMedCrossRef

Scanga DR, Martin WH, Delbeke D. Value of FDG PET imaging in the management of patients with thyroid, neuroendocrine, and neural crest tumors. Clin Nucl Med 2004;29:86–90PubMedCrossRef

Avril NE, Weber WA. Monitoring response to treatment in patients utilizing PET. Radiol Clin North Am 2005;43:189–204PubMedCrossRef

Lyons SK. Advances in imaging mouse tumour models in vivo. J Pathol 2005;205:194–205PubMedCrossRef

Herschman HR. Micro-PET imaging and small animal models of disease. Curr Opin Immunol 2003;15:378–384PubMedCrossRef

Roselt P, Meikle S, Kassiou M. The role of positron emission tomography in the discovery and development of new drugs; as studied in laboratory animals. Eur J Drug Metab Pharmacokinet 2004;29:1–6PubMedCrossRef

10.

Maschauer S, Prante O, Hoffmann M, Deichen JT, Kuwert T. Characterization of¹⁸F-FDG uptake in human endothelial cells in vitro. J Nucl Med 2004;45:455–460PubMed

11.

Rajendran JG, Wilson DC, Conrad EU, Peterson LM, Bruckner JD, Rasey JS, et al. [¹⁸F]FMISO and [¹⁸F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging 2003;30:695–704PubMedCrossRef

12.

Plas DR, Thompson CB. Cell metabolism in the regulation of programmed cell death. Trends Endocrinol Metab 2002;13:75–78PubMedCrossRef

13.

Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004;64:3892–3899PubMedCrossRef

14.

Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo validation of 3'deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) as a proliferation imaging tracer in humans: correlation of [¹⁸F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 2002;8:3315–3323PubMed

15.

Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–1336PubMedCrossRef

16.

Piert M, Machulla H-J, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxia-specific tumor imaging with¹⁸F-fluoroazomycin arabinoside. J Nucl Med 2005;46:106–113PubMed

17.

Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, et al. [¹⁸F]fluoroazomycinarabinofuranoside (¹⁸FAZA) and [¹⁸F]fluoromisonidazole (¹⁸FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol 2003;30:317–326PubMedCrossRef

18.

Grierson JR, Schwartz JL, Muzi M, Jordan R, Krohn KA. Metabolism of 3'-deoxy-3'-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. Nucl Med Biol 2004;31:829–837PubMedCrossRef

19.

Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3'-deoxy-3'-[¹⁸F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791–3798PubMed

20.

Bradshaw HD Jr. Molecular cloning and cell cycle-specific regulation of a functional human thymidine kinase gene. Proc Natl Acad Sci U S A 1983;80:5588–5591PubMedCrossRef

21.

Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;263:8350–8358PubMed

22.

Nunn A, Linder K, Strauss HW. Nitroimidazoles and imaging hypoxia. Eur J Nucl Med 1995;22:265–280PubMedCrossRef

23.

Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001;93:266–276PubMedCrossRef

24.

Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–2459PubMedCrossRef

25.

Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW et al. Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer 2004;91:1532–1542PubMedCrossRef

26.

Ioachim E, Kamina S, Athanassiadou S, Agnantis NJ. The prognostic significance of epidermal growth factor receptor (EGFR), C-erbB-2, Ki-67 and PCNA expression in breast cancer. Anticancer Res 1996;16(5B):3141–3147PubMed

27.

Tsuda H, Morita D, Kimura M, Shinto E, Ohtsuka Y, Matsubara O et al. Correlation of KIT and EGFR overexpression with invasive ductal breast carcinoma of the solid-tubular subtype, nuclear grade 3, and mesenchymal or myoepithelial differentiation. Cancer Sci 2005;96:48–53PubMedCrossRef

28.

Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354PubMedCrossRef

29.

Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW. Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 2002;29:11–21PubMed

30.

Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 2001;28:80–85PubMedCrossRef

31.

Smaill JB, Rewcastle GW, Loo JA, Greis KD, Chan OH, Reyner EL, et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 2000;43:1380–1397PubMedCrossRef

32.

Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang X-Y, James CD, et al. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 2001;61:739–748PubMed

33.

Nyati MK, Maheshwari D, Hanasoge S, Sreekumar A, Rynkiewicz SD, Chinnaiyan AM, et al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin Cancer Res 2004;10:691–700PubMedCrossRef

34.

Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson JR. Simplified labeling approach for synthesizing 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FET). J Radioanal Nucl Chem 2000;243:843–846CrossRef

35.

Piert M, Machulla HJ, Kumar P, Link T, Wiebe LI.¹⁸F labeled fluoroazamycin arabinoside (FAZA): a novel marker of tumour tissue hypoxia. J Nucl Med 2001;42:279

36.

Surti S, Karp JS, Perkins AE, Freifelder R. TNSG. M. Design evaluation of A-PET: A high sensitivity animal PET camera. Trans Nucl Sci 2003;50:1357–1363CrossRef

37.

Chiang S, Cardi C, Matej S, Zhuang H, Newberg A, Alavi A, et al. Clinical validation of fully 3-D versus 2.5-D RAMLA reconstruction on the Philips-ADAC CPET PET scanner. Nucl Med Commun 2004;25:1103–1107PubMedCrossRef

38.

Tanaka E, Kudo H. Subset-dependent relaxation in block-iterative algorithms for image reconstruction in emission tomography. Phys Med Biol 2003;48:1405–1422PubMedCrossRef

39.

Deans AJ, Simpson KJ, Trivett MK, Brown MA, McArthur GA. Brca1 inactivation induces p27(Kip1)-dependent cell cycle arrest and delayed development in the mouse mammary gland. Oncogene 2004;23:6136–6145PubMedCrossRef

40.

Stuart P, Ito M, Stewart C, Conrad SE. Induction of cellular thymidine kinase occurs at the mRNA level. Mol Cell Biol 1985;5:1490–1497PubMed

41.

Solomon B, Hagekyriakou J, Trivett MK, Stacker SA, McArthur GA, Cullinane C. EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Epidermal growth factor receptor. Int J Radiat Oncol Biol Phys 2003;55:713–723PubMedCrossRef

42.

Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000;6:4885–4892PubMed

43.

Avril N. GLUT1 expression in tissue and¹⁸F-FDG uptake. J Nucl Med 2004;45:930–932PubMed

44.

Mueckler M. Facilitative glucose transporters. Eur J Biochem 1994;219:713–725PubMedCrossRef

45.

Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y. Basis of FLT as a cell proliferation marker: comparative uptake studies with [³H]thymidine and [³H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29:281–287PubMedCrossRef

46.

Guppy M. The hypoxic core: a possible answer to the cancer paradox. Biochem Biophys Res Commun 2002;299:676–680PubMedCrossRef

47.

Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 1994;6:509–518PubMed

48.

Anderson NG, Ahmad T, Chan K, Dobson R, Bundred NJ. ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer 2001;94:774–782PubMedCrossRef

49.

Matar P, Rojo F, Cassia R, Moreno-Bueno G, Di Cosimo S, Tabernero J, et al. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 2004;10:6487–6501PubMedCrossRef

50.

Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005;202:654–662PubMedCrossRef

51.

Mischoulon D, Rana B, Kotliar N, Pilch PF, Bucher NL, Farmer SR. Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes. J Cell Physiol 1992;153:288–296PubMedCrossRef

52.

Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB. Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem 2002;277:11392–11400PubMedCrossRef

53.

Waldherr C, Mellinghoff IK, Tran C, Halpern BS, Rozengurt N, Safaei A, et al. Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18 F-fluorothymidine PET. J Nucl Med 2005;46:114–120PubMed

54.

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;43:1210–1217PubMed

55.

Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;263:8350–8358PubMed

56.

Lin L, Kuroiwa N, Moriyama Y, Fujimura S. Continuous increase in phosphorylation of cytosolic thymidine kinase during proliferation of rat hepatoma JB1 cells. Oncol Rep 2003;10:665–669PubMed

57.

58.

Gerdes J, Becker MH, Key G, Cattoretti G. Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues. J Pathol 1992;168:85–86PubMedCrossRef

59.

Nelson JM, Fry DW. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem 2001;276:14842–14847PubMedCrossRef

60.

Broker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res 2005;11:3155–3162PubMedCrossRef

61.

Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia 2005;7:324–330PubMedCrossRef

62.

Solomon B, Binns D, Roselt P, Weibe LI, McArthur GA, Cullinane C, et al. Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Mol Cancer Ther 2005;4:1417–1422PubMedCrossRef

63.

Russell KS, Stern DF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol 1999;277:H2205–H2211PubMed

64.

Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997;151:1523–1530PubMed

Titel: Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033
verfasst von: Donna S. Dorow
Carleen Cullinane
Nelly Conus
Peter Roselt
David Binns
Timothy J. McCarthy
Grant A. McArthur
Rodney J. Hicks
Publikationsdatum: 01.04.2006
Verlag: Springer-Verlag
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 4/2006
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-005-0039-5

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033

Abstract

Purpose

Methods

Results

Conclusion

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2006

PET imaging of brain astrocytoma with 1-11C-acetate

The immune system and cancer: the evolving role of molecular imaging and molecular targeted therapy

Synthesis of 99mTc-HYNIC-interleukin-12, a new specific radiopharmaceutical for imaging T lymphocytes

No-carrier-added versus carrier-added123I-metaiodobenzylguanidine for the assessment of cardiac sympathetic nerve activity

Uptake of bone-seekers is solely associated with mineralisation! A study with 99mTc-MDP, 153Sm-EDTMP and 18F-fluoride on osteoblasts

Use of 3′-deoxy-3′-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors