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European Journal of Nuclear Medicine and Molecular Imaging

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01-08-2006 | Original article

Differentiation of tumour and inflammation: characterisation of [methyl-³H]methionine (MET) and O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells

Authors: Barbara Stöber, Ursula Tanase, Michael Herz, Christof Seidl, Markus Schwaiger, Reingard Senekowitsch-Schmidtke

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 8/2006

Abstract

Purpose

Previous studies suggest that radiolabelled amino acids could be superior to FDG in differentiating tumour and inflammation. Therefore the aim of this study was to investigate the uptake of FET and MET in human tumour and inflammatory cells and to investigate their uptake kinetics.

Methods

For uptake studies, cells were incubated with 370 kBq FET or 3.7 kBq MET for 15 min. Kinetic studies were performed at variable concentrations of FET and MET. Competitive inhibition studies were done with BCH, MeAIB and L-serine.

Results

All inflammatory cells incorporated more MET than the tumour cells. The uptake of FET, in contrast, was significantly lower in all inflammatory cells than in the tumour cells. In tumour cells the uptake of MET was about five times the uptake of FET. The competitive inhibitors reduced uptake of both tracers to 20–40% in tumour cells and to 70% in inflammatory cells. Kinetic studies showed that MET and FET transport was saturable in all cells except macrophages and followed a Michaelis-Menten kinetic. Highest capacity (V _max) and affinity (K _m) for the uptake of MET was observed in granulocytes. Capacity and affinity for FET uptake were highest in the DHL-4 cells.

Conclusion

In contrast to MET, FET accumulated to a significantly greater extent in tumour cells than in inflammatory cells. The marked differences between tumour and inflammatory cells concerning FET and MET uptake suggest that FET and MET are substrates of different subtypes of the L system.

Larson SM. Cancer or inflammation? A holy grail for nuclear medicine. J Nucl Med 1994;35:1653–1654PubMed

Bakheet SM, Powe J. Benign causes of 18-FDG uptake on whole body imaging. Semin Nucl Med 1998;28:352–358PubMedCrossRef

Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluordeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992;33:1972–1980PubMed

Kubota K, Kubota R, Yamada S, Tada M. Effects of radiotherapy on the cellular uptake of carbon-14-labeledL-methionine in tumor tissue. Nucl Med Biol 1995;22:193–198CrossRefPubMed

Kubota R, Kubota K, Yamada S, Tada M, Iwata R, Tamahashi N. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med 1995;36:484–492PubMed

Yamada S, Kubota K, Kubota R, Ido T, Tamahashi N. High accumulation in fluorine-18-fluorodeoxyglucose in turpentine-induced inflammatory tissue. J Nucl Med 1995;36:1301–1306PubMed

Sugawara Y, Gutowski TD, Fisher SJ, Brown R, Wahl RL. Uptake of positron emission tomography tracers in experimental bacterial infections: a comparative biodistribution study of radiolabeled FDG, thymidine andL-methionine,⁶⁷Ga-citrate and¹²⁵I-HAS. Eur J Nucl Med 1999;26:333–341CrossRefPubMed

Reinhardt MJ, Kubota K, Yamada S, Iwata R, Yaegashi H. Assessment of cancer recurrence in residual tumors after fractionated radiotherapy: a comparison of fluordeoxyglucose,L-methionine and thymidine. J Nucl Med 1997;38:280–287PubMed

Gutowski TD, Fisher SJ, Moon R, Wahl RL. Experimental studies of¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) in infection and in reactive lymph nodes [abstract]. J Nucl Med 1992;33:925

10.

Wahl RL, Fisher SJ. A comparison of FDG,L-methionine and thymidine accumulation into experimental infections and reactive lymph nodes [abstract]. J Nucl Med 1993;34:104PubMed

11.

Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. Investigation of transport mechanism and uptake kinetics ofO-(2-[¹⁸F]fluoroethyl)-L-tyrosine in vitro and in vivo. J Nucl Med 1999;40:1367–1373PubMed

12.

Laverman P, Boerman OC, Corstens FH, Oyen WJ. Fluorinated amino acids for tumour imaging with positron emission tomography. Eur J Nucl Med Mol Imaging 2002;29:681–690CrossRefPubMed

13.

Jager PL, Vaalburg W, Pruim J, de Vries EG, Langen KJ, Piers DA. Radiolabeled amino acids: basic aspects and clinical applications in oncology. J Nucl Med 2001;42:432–445PubMed

14.

Samnick S, Hellwig D, Gouverneur E, Romeike BF, Schneider G, Menger M, et al Evaluation of radioiodinated phenylalanine-analogues as radiopharmaceuticals to image pancreatic carcinomas in in-vivo models of human pancratic tumors. Eur J Nucl Med Mol Imaging 2003;30 Suppl 2:S175

15.

Langen KJ, Ziemons K, Kiwit CW, Herzog H, Kuwert T, Bock WJ, et al 3-[I-123]iodo-α-methyltyrosine and [methyl-C-11]-L-methionine uptake in cerebral gliomas: a comparative study using SPECT and PET. J Nucl Med 1997;38:517–522PubMed

16.

Leskinen-Kallio S, Ruotsalainen U, Nagren K, Teras M, Joensuu H. Uptake of carbon-11-methionine and fluorodeoxyglucose in non-Hodgkin’s lymphoma: a PET study. J Nucl Med 1991;32:1211–1218PubMed

17.

Nettelbladt OS, Sundin AE, Valind SO, Gustafsson GR, Lamberg K, Lagström B, et al Combined fluorine-18-FDG and carbon-11-methionine PET for diagnosis of tumors in lung and mediastinum. J Nucl Med 1998;39:640–647PubMed

18.

Leskinen-Kallio S, Nagren K, Lehikoinen P, Ruotsalainen U, Joensuu H. Uptake of C-11-methionine in breast cancer studied by PET: an association with the size of S-phase fraction. Br J Cancer 1991;64:1121–2214PubMed

19.

Kole AC, Plaat BE, Hoekstra HJ, Vaalburg W, Molenaar WM. FDG andL-[1-¹¹C]-tyrosine imaging of soft-tissue tumors before and after therapy. J Nucl Med 1999;40:381–386PubMed

20.

Tomiyoshi K, Inoue T, Higuchi T, Ahmed K, Sarwar M, Alyafei S, et al Metabolic studies of [F-18-alpha-methyl]tyrosine in mice bearing colorectal carcinoma LS-180. Anitcancer Drugs 1999;10:329–336CrossRef

21.

Langen KJ, Jarosch M, Hamacher K, Muhlensiepen H, Weber F, Floeth F, Pauleit D, Herzog H, Coenen HH. Imaging of gliomas with Cis-4-[¹⁸F]fluoro-L-proline. Nucl Med Biol 2004;31:67–75CrossRefPubMed

22.

Langen KJ, Jarosch M, Mühlensiepen H, Hamacher K, Broer S, Jansen P, et al Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas. Nucl Med Biol 2003;30:501–508CrossRefPubMed

23.

Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al Synthesis and radiopharmacology ofO-(2-[¹⁸F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med 1999;40:205–212PubMed

24.

Weber WA, Wester HJ, Grosu AL, Herz M, Dzewas B, Feldmann HJ, et alO-(2-[¹⁸F]fluoroethyl)-L-tyrosine andL-[methyl-¹¹C]methionine uptake in brain tumors: initial results of a comparative study. Eur J Nucl Med Mol Imaging 2000;27:542–549CrossRef

25.

Rau FC, Weber WA, Wester HJ, Herz M, Becker I, Krüger A, et al O-(2-[¹⁸F]Fluoroethyl)-L-tyrosine (FET): a tracer for diferentiation of tumour from inflammation in murine lymph nodes. Eur J Nucl Med Mol Imaging 2002;29:1039–1046CrossRefPubMed

26.

Pöpperl G, Götz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K. Value ofO-(2-[¹⁸F]fluoroethyl)-L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging 2004;31:1464–1470CrossRefPubMed

27.

Weckesser M, Langen KJ, Rickert CH, Kloska S, Straeter R, Hamacher K, et alO-(2-[¹⁸F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging 2005;32:422–429CrossRefPubMed

28.

Kaim AH, Weber B, Kurrer MO, Westera G, Schweitzer A, Gottschalk J, et al ¹⁸F-FDG and ¹⁸F-FET uptake in experimental soft tissue infection. Eur J Nucl Med Mol Imaging 2002;29:648–654CrossRefPubMed

29.

Pauleit D, Floeth F, Tellmann L, Hamacher K, Hautzel H, Müller HW, et al Comparison ofO-(2-¹⁸F-fluoroethyl)-L-tyrosine PET and 3-¹²³I-iodo alpha-methyl-L-tyrosine SPECT in brain tumors. J Nucl Med 2004;45:374–381PubMed

30.

Ishiwata K, Kubota K, Murakami M, Kubota R, Sasaki T, Ishii S, et al Re-evaluation of amino acid PET studies: can the protein synthesis rates in brain and tumor tissues be measured in vivo? J Nucl Med 1993;34:1936–1943PubMed

31.

Tahara T, Ichiya Y, Kuwabara Y. High fluorodeoxyglucose uptake in abdominal abscesses: a PET study. J Comput Assist Tomog 1989;13:829–831CrossRef

32.

Meyer MA, Frey KA, Schwaiger M. Discordance between F-18 fluordeoxyglucose uptake and contrast enhancement in a brain abscess. Clin Nucl Med 1993;18:682–684PubMedCrossRef

33.

Kubota K, Matsuzawa T, Fumiwata T. Differential diagnosis of lung tumor with positron emission tomography: a prospective study. J Nucl Med 1990;31:1927–1933PubMed

34.

Lowe VJ, Naunheim KS. Positron emission tomography in lung cancer. Ann Thorac Surg 1998;65:1821–1829CrossRefPubMed

35.

Suguwara Y, Braun DK, Kison PV, Russo JE, Zasadny KR, Wahl RL. Rapid detection of human infections with fluorine-18-fluorodeoxyglucose and positron emission tomography: preliminary results. Eur J Nucl Med 1998;25:1238–1243CrossRefPubMed

36.

Guhlmann A, Brecht-Krauss D, Suger G, Glatting G, Kotzerke J, Kinzl L, et al Fluorine-18-FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis. J Nucl Med 1998;39:2145–2152PubMed

37.

Spaeth N, Wyss MT, Weber B, Scheidegger S, Lutz A, Verwey J, et al Uptake of ¹⁸F-fluorocholine, ¹⁸F-fluoroethyl-L-tyrosine, and ¹⁸F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl Med 2004;45:1931–1938PubMed

38.

Pauleit D, Stoffels G, Schaden W, Hamacher K, Bauer D, Tellmann L, et al PET withO-(2-¹⁸F-fluoroethyl)-L-tyrosine in peripheral tumors: first clinical results. J Nucl Med 2005;46:411–416PubMed

39.

Kubota K, Matsuzawa T, Fujiwara T, Sato T, Tada M, Ido T, Ishiwata K. Differential diagnosis of AH 109 A tumor and inflammation by radioscintigraphy withL-[methyl-¹¹C]methionine. Jpn J Cancer Res 1989;80:778–782PubMed

40.

Pauleit D, Floeth F, Herzog H, Hamacher K, Tellmann L, Müller HW, Coenen HH, Langen KJ. Whole-body distribution and dosimety ofO-(2-[¹⁸F]fluoroethyl)-L-tyrosine. Eur J Nucl Med Mol Imaging 2003;30:519–524PubMedCrossRef

41.

Shotwell MA, Kilberg MS, Oxender DL. The regulation of neutral amino acid transport in mammalian cells. Biochim Biophys Acta 1983;737:267–284PubMed

42.

Saier MH, Daniels GA, Boerner P, Lin J. Neutral amino acid transport systems in animal cells: potential targets of oncogene action and regulators of cellular growth. J Membr Biol 1988;104:1–20CrossRefPubMed

43.

Segel GB, Woodlock TJ, Murant FG, Lichtman MA. Photoinhibition of 2-amino-2-carboxybicyclo[2,2,1]heptane transport byO-diazoacetyl-L-serine. An initial step in identifying the L-system amino acid transporter. J Biol Chem 1989;264:16399–402PubMed

44.

Barker GA, Wilkins RJ, Golding S, Ellory JC. Neutral amino acid transport in bovine articular chondrocytes. J Physiol 1999;514:795–808CrossRefPubMed

45.

Jara JR, Martinez-Liarte JH, Solano F, Penafiel R. Transport ofL-tyrosine by B16/F10 melanoma cells: the effect of the intracellular content of other amino acids. J Cell Sci 1990;97:479–485PubMed

46.

Pankovich JM, Jimbow K. Tyrosine transport in a human melanoma cell line as a basis for selective transport of cytotoxic analogues. Biochem J 1991;280:721–725PubMed

47.

Langen KJ, Pauleit D, Coenen HH. 3-[¹²³I]Iodo-alpha-methyl-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol 2002;29:625–631CrossRefPubMed

48.

Verrey F. System L: heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflugers Arch 2003;445:529–533PubMed

49.

Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 1990;70:43–77PubMed

50.

Scanion K, Berkowitz K, Pallai M, Waxman S. Inhibition of methionine transport by methotrexate in mitogen stimulated human lymphocytes. Cancer Treat Rep 1983;67:631–639PubMed

51.

Rau FC, Philippi H, Rubio-Aliaga I, Daniel H, Weber A, Schwaiger M, et al Identification of subtypes of amino acid transporters in human tumor and inflammatory cells by reverse transcription-polymerase chain reaction [abstract]. J Nucl Med 2002;43(suppl):24

52.

Verrey F, Meier C, Rossier G, Kuehn LC. Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity. Eur J Physiol 2000;440:503–512CrossRef

53.

Su TZ, Lunney E, Campbell G, Oxender DL. Transport of gabapentin, a gamma-amino acid drug, by system L alpha-amino acid transporters: a comparative study in astrocytes, synaptosomes and CHO cells. J Neurochem 1995;64:2125–2131PubMedCrossRef

54.

Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, et al Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 2001;1514:291–302PubMedCrossRef

55.

Shennan DB, Thomson J, Barber MC, Travers MT. Functional and molecular characteristics of system L in human breast cancer cells. Biochim Biophys Acta 2003;1611:81–90PubMedCrossRef

56.

Ohkame H, Masuda H, Ishii Y, Kanai Y. Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models. J Surg Oncol 2001;78:265–271CrossRefPubMed

57.

Meier C, Ristic Z, Klauser S, Verrey F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J 2002;21:580–589CrossRefPubMed

58.

Lahoutte T, Caveliers v, Camargo S, Franca R, Ramadan T, Veljkovic E, Mertens J, et al SPECT and PET amino acid tracer influx via system L (h4F2hc-hLAT1) and its transstimulation. J Nucl Med 2004;45:1591–1596PubMed

59.

Babu E, Kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, et al Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 2003;278:43838–43845CrossRefPubMed

60.

Collarini EJ, Campbell GS, Oxender DL. Evidence for a regulatory element controlling amino acid transport system L in Chinese hamster ovary cells. J Cell Biochem 1994;56:544–549CrossRefPubMed

61.

Shotwell MA, Jayme DW, Kilberg MS, Oxender DL. Neutral amino acid transport system in Chinese hamster ovary cells. J Biol Chem 1981;256:5422–5427PubMed

62.

Mitsumoto Y, Sato K, Ohyashiki T, Mohri T. Leucine-proton cotransport system in Chang liver cell. J Biol Chem 1983;261:4549–4554

63.

Rajan DP, Kekuda R, Huang W, Devoe LD, Leibach FH, Prasad PD, et al Cloning and functional characterization of a Na⁺-independent, broad-specific neutral amino acid transporter from mammalian intestine. Biochim Biophys Acta 2001;463:6–14

Title: Differentiation of tumour and inflammation: characterisation of [methyl-3H]methionine (MET) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells
Authors: Barbara Stöber
Ursula Tanase
Michael Herz
Christof Seidl
Markus Schwaiger
Reingard Senekowitsch-Schmidtke
Publication date: 01-08-2006
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 8/2006
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-005-0047-5

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Differentiation of tumour and inflammation: characterisation of [methyl-³H]methionine (MET) and O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells

Abstract

Purpose

Methods

Results

Conclusion

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Abstract

Purpose

Methods

Results

Conclusion

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