Molekulare Bildgebung der Proliferation mit [¹⁸F]FLT-PET

Zusammenfassung

Eine gesteigerte Proliferationsrate ist ein wesentliches Charakteristikum maligne transformierter Zellen und daher für eine spezifische Darstellung bösartiger Tumore potentiell besser geeignet als Alterationen des Glukose-Stoffwechsels. Da therapeutische Ansätze in der Onkologie überwiegend auf eine gesteigerte Proliferation zielen, ist die nicht-invasive Bestimmung der proliferativen Aktivität auch zur Beurteilung des Therapieansprechens und frühzeitigen Erkennung einer Therapieresistenz von besonderem Interesse. In klinischen Studien zeigte sich eine spezifische Anreicherung des Radionukleosids 3′-Desoxy-3′-[¹⁸F]Fluorthymidin (FLT) in malignen Tumoren. Es konnte für eine Vielzahl solider Malignome gezeigt werden, dass mit FLT-PET eine nicht-invasive Beurteilung der proliferativen Aktivität möglich ist. Die lineare Regressionsanalyse der tumoralen FLT-Anreicherung und der immunhistochemisch ermittelten Proliferationsfraktion (PCNA, Ki-67 Index) ergab eine signifikante Korrelation (z. B. Lungenkarzinom, r=0,87, p<0,0001). Im direkten Vergleich mit dem Standardradiopharmakon FDG konnte gezeigt werden, dass FLT die histologisch bestimmte Proliferationsrate exakter widerspiegelt. Malignome mit geringer proliferativen Aktivität entgingen jedoch der Detektion mit FLT-PET. Bei malignen Lungentumoren wurde z. B. eine reduzierte Sensitivität von 86% beschrieben. Aufgrund der eingeschränkten Sensitivität ergibt sich für das Staging des Lungenkarzinoms oder kolorektaler Karzinome kein Vorteil für die spezifische Bildgebung der proliferativen Aktivität. Auch hinsichtlich der Detektion von lokoregionären Lymphknoten- und Fernmetastasen weist die FDG-PET eine höhere Sensitivität auf. Lediglich bei Hodgkin- und Non-Hodgkin-Lymphomen zeigte die FLT-PET eine vergleichbare Sensitivität. Eine Spezifität von 100% deutet darauf hin, dass mit FLT-PET eine Methode zur Verfügung steht, mit der nicht-invasiv die proliferative Aktivität sämtlicher Lymphom-Manifestationen beurteilt und gezielt Biopsien entnommen werden können. Dies hat potentiell eine Bedeutung für die Therapieplanung, da sämtliche Lokalisationen auf das Vorliegen einer gesteigerten Proliferationsrate und somit einer möglichen Transformation zu einer aggressiveren Histologie untersucht werden können. Da Chemotherapie und Strahlentherapie eine Schädigung der Zellen verursachen, welche zum Zeitpunkt der Therapie den Zellzyklus durchlaufen, könnte mit FLT-PET eine einfache und frühzeitige Beurteilung des Therapieerfolges ermöglicht werden. Erste In-vitro- und In-vivo-Studien konnten eine rasche Reduktion der FLT-Aufnahme nach Einleitung einer zytostatischen Therapie nachweisen. In Maus-Xenotransplantatmodellen war bereits 24 h nach Chemotherapie eine signifikante Reduktion der FLT-Anreicherung im Tumor messbar. Mit FLT-PET lässt sich somit die gesteigerte Proliferation als Charakteristikum maligner Tumore nicht-invasiv erfassen. Ob hiermit eine entscheidende Zusatzinformation im Vergleich zu dem Standard-Radiopharmakon FDG generiert werden kann, muss in weiteren In-vitro-Experimenten und klinischen Studien gezeigt werden.

Abstract

An increased proliferation fraction is a hallmark of malignant cells and a specific feature of malignant tumors which potentially allows more specific tumor imaging compared to increased glucose consumption (FDG-PET). The majority of therapeutic approaches aim at inhibition of proliferation or induction of apotposis. Accordingly, non-invasive assessment of the proliferation fraction is also of interest for montoring response to treatment and to early detect resistance to a specific kind of therapy. In clinical studies it has been demonstrated that the radiotracer 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) accumulates specifically in malignant tumors. Regression analysis of tumoral FLT-uptake and immunohistochemically detected proliferation fraction (PCNA, Ki-67) resulted in a significant correlation (e.g., in lung cancer, correlation coefficient r=0.87, p<0.0001). The possibility to non-invasively assess the proliferation fraction with FLT-PET has been shown in a variety of solid cancers. Compared to the standard radiotracer FDG, superior demonstration of the proliferative activity using FLT as the tracer has been demonstrated. On the other hand, accumulation of FLT was significantly lower compared to FDG. Malignant tumors with low proliferation rates did not present with increased FLT-uptake resulting in a reduced sensitivity. In lung cancer for example, the sensitivity was 86% of FLT-PET compared to 100% of FDG-PET. Also, regarding detection of locoregional lymph node metastases or distant metastases, FDG-PET was shown to have a higher sensitivity. Due to the reduced sensitivity, there is no advantage of specific imaging of tumor proliferation regarding tumor staging. In malignant lymphoma, FLT was similar effective for tumor staging as compared to FDG-PET. In a pilot study comprising 34 patients, both tracers showed a similar sensitivity regarding detection of lymphoma. An observed specificity of 100% indicates that FLT-PET represents a diagnostic test for non-invasive assessment of the proliferation fraction in malignant lymphoma which can be used to further guide biopsy of lesions and subsequent tumor grading. This has potential impact on the therapeutic decision making process since all localizations can be evaluated regarding an increased proliferation fraction and transformation to a more aggressive histology. Chemotherapy and radiotherapy induce damage to tumor cells which are passing through the cell cycle at the time point of treatment. Therefore, FLT-PET could be a suitable approach for early response monitoring. Initial in-vitro and in-vivo studies demonstrated a rapid reduction of tumoral FLT-uptake early in the course of cytostatic or cytotoxic treatment. In mouse xenotransplant models, cytostatic drug effects have been demonstrated by a marked reduction of the FLT-uptake as early as 24 h after initiation of therapy. FLT-PET therefore represents a suitable tool to non-invasively assess the increased proliferative activity which is a prerequisite of malignant tumors. Whether the radiotracer FLT offers incremental diagnosis information compared to FDG-PET remains to be determined.

Positronenemissionstomografie - Radionukleoside - [¹⁸F]FLT - Onkologie - Staging - Grading - therapeutisches Ansprechen - Therapiemanagement

positron emission tomography - radionucleosides - [¹⁸F]FLT - oncology - staging - grading - response monitoring - therapeutic management

Literatur

• 1 Apisarnthanarax S, Alauddin MM, Mourtada F. et al . Early detection of chemoradioresponse in esophageal carcinoma by 3’-deoxy-3’-³H-fluorothymidine using preclinical tumor models.  Clin Cancer Res. 2006;  12 4590-4597
• 2 Barthel H, Cleij MC, Collingridge DR. et al . 3’-deoxy-3’-[¹⁸F]fluoro-thymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography.  Cancer Res. 2003;  63 3791-3798
• 3 Barthel H, Perumal M, Latigo J. et al . The uptake of 3’-deoxy-3’-[¹⁸F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels.  Eur J Nucl Med Mol Imaging. 2005;  32 257-263
• 4 Been LB, Suurmeijer AJ, Elsinga PH. et al . ¹⁸F -fluorodeoxythymidine PET for evaluating the response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcomas.  J Nucl Med. 2007;  48 367-372
• 5 Bergstrom M, Lu L, Fasth KJ. et al . In vitro and animal validation of bromine-76-bromodeoxyuridine as a proliferation marker.  J Nucl Med. 1998;  39 1273-1279
• 6 Blagosklonny MV, Pardee AB. Exploiting cancer cell cycling for selective protection of normal cells.  Cancer Res. 2001;  61 4301-4305
• 7 Bos R, Hoeven JJ van Der, Wall E van Der. et al . Biologic correlates of ¹⁸F-fluoro-deoxyglucose uptake in human breast cancer measured by positron emission tomography.  J Clin Oncol. 2002;  20 379-387
• 8 Brown RS, Leung JY, Kison PV. et al . Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer.  J Nucl Med. 1999;  40 556-565
• 9 Buck AK, Schirrmeister H, Guhlmann CA. et al . Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity?.  J Nucl Med. 2001;  42 721-725
• 10 Buck AK, Schirrmeister H, Hetzel M. et al . ¹⁸F]FLT-PET for non-invasive assessment of proliferation in pulmonary nodules.  Cancer Res. 2002;  62 3331-3334
• 11 Buck AK, Schirrmeister H, Kühn T. et al . FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters.  Eur J Nucl Med. 2002;  29 1317-1323
• 12 Buck AK, Halter G, Schirrmeister H. et al . Functional imaging of pulmonary nodules with FDG and FLT-PET.  J Nucl Med. 2003;  44 1426-1431
• 13 Buck AK, Hetzel M, Schirrmeister H. et al . Clinical relevance of imaging proliferative activity in lung nodules.  Eur J Nucl Med Mol Imaging. 2005;  32 525-533
• 14 Buck AK, Bommer M, Stilgenbauer S. et al . Molecular imaging of proliferation in malignant lymphoma.  Cancer Res. 2006;  66 11055-11061
• 15 Buck AK, Herrmann K, Büschenfelde CM. et al . Imaging bone and soft tissue tumors with the proliferation marker [¹⁸F]fluorodeoxythymidine.  Clin Cancer Res. 2008;  15 2970-2977
• 16 Buck AK, Bommer M, Juweid ME. et al . First demonstration of leukemia imaging with the proliferation marker ¹⁸F-fluorodeoxythymidine.  J Nucl Med. 2008;  49 1756-1762
• 17 Bunz F, Dutriaux A, Lengauer C. et al . Requirement for p53 and p21 to sustain G2 arrest after DNA damage.  Science. 1998;  282 1497-1501
• 18 Caraco C, Aloj L, Chen LY. et al . Cellular release of [¹⁸F]-2-fluoro-2-deoxyglucose as a function of the glucose-6-phosphatase enzyme system.  J Biol Chem. 2000;  275 18489-18494
• 19 Cass CE, Young JD, Baldwin SA. Recent advances in the molecular biology of nucleoside transporters of mammalian cells.  Biochem Cell Biol. 1998;  76 761-770
• 20 Chen W, Delaloye S, Silverman DH. et al . Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [¹⁸F]fluorothymidine positron emission tomography: a pilot study.  J Clin Oncol. 2007;  25 4714-4721
• 21 Choi SJ, Kim JS, Kim JH. et al . [¹⁸F]3’-deoxy-3’-fluorothymidine PET for the diagnosis and grading of brain tumors.  Eur J Nucl Med Mol Imaging. 2005;  32 653-659
• 22 Cobben DC, Elsinga PH, Suurmeijer AJ. et al . Detection and grading of soft tissue sarcomas of the extremities with ¹⁸F-3’-fluoro-3’-deoxy-L-thymidine.  Clin Cancer Res. 2004;  10 1685-1690
• 23 Diederichs CG, Staib L, Glasbrenner B. et al . F-18 fluorodeoxyglucose (FDG) and C-reactive protein (CRP).  Clin Positron Imaging. 1999;  2 131-136
• 24 Dittmann H, Dohmen BM, Kehlbach R. et al . Early changes in [¹⁸F]FLT uptake after chemotherapy: an experimental study.  Eur J Nucl Med Mol Imaging. 2002;  29 1462-1469
• 25 Dosaka-Akita H, Hommura F, Mishina T. et al . A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis.  Cancer Res. 2001;  15 2500-2504
• 26 Francis DL, Visvikis D, Costa DC. et al . Potential impact of [¹⁸F]3’-deoxy-3’-fluorothymidine versus [¹⁸F]fluoro-2-deoxy-D-glucose in positron emission tomography for colorectal cancer.  Eur J Nucl Med Mol Imaging. 2003;  30 988-994
• 27 Francis DL, Freeman A, Visvikis D. et al . In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography.  Gut. 2003;  52 1602-1606
• 28 Graf N, Herrmann K, den Hollander J. et al . Imaging proliferation to monitor early response of lymphoma to cytotoxic treatment.  Mol Imaging Biol. 2008;  10 349-355
• 29 Herrmann K, Wieder HA, Buck AK. et al . Early response assessment using 3’-deoxy-3’-[¹⁸F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin's lymphoma.  Clin Cancer Res. 2007;  13 3552-3558
• 30 Herrmann K, Eckel F, Schmidt S. et al . In vivo characterization of proliferation for discriminating cancer from pancreatic pseudotumors.  J Nucl Med. 2008;  49 1437-1444
• 31 Herrmann K, Ott K, Buck AK. et al . Imaging gastric cancer with PET and the radiotracers ¹⁸F-FLT and ¹⁸F-FDG: a comparative analysis.  J Nucl Med. 2007;  48 1945-1950
• 32 Higashi K, Clavo A, Wahl R. Does FDG uptake measure proliferative activity of human cancer cells? In vitro comparison with DNS flow cytometry and tritiated thymidine uptake.  J Nucl Med. 1993;  34 414-419
• 33 Higashi K, Ueda Y, Yagishita M. et al . FDG PET measurement of the proliferative potential of non-small cell lung cancer.  J Nucl Med. 2000;  41 85-92
• 34 Hommura F, Dosaka-Akita H, Mishina T. et al . Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers.  Clin Cancer Res. 2000;  10 4073-4081
• 35 Jacobs AH, Thomas A, Kracht LW. et al . 18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors.  J Nucl Med. 2005;  46 1948-1958
• 36 Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy.  N Engl J Med. 2006;  35 496-507
• 37 Kasper B, Egerer G, Gronkowski M. et al . Functional diagnosis of residual lymphomas after radiochemotherapy with positron emission tomography comparing FDG- and FLT-PET.  Leuk Lymphoma. 2007;  48 746-753
• 38 Kenny LM, Vigushin DM, Al-Nahhas A. et al . Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [¹⁸F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods.  Cancer Res. 2005;  65 10104-10112
• 39 Kim EY, Vrang L, Oberg B. et al . Anti-HIV type 1 activity of 3’-fluoro-3’-deoxythymidine for several different multidrug-resistant mutants.  AIDS Res Hum Retroviruses. 2001;  17 401-407
• 40 Kubota R, Ishiwata K, Kubota R. et al . Tracer feasibility for monitor-ing tumor radiotherapy; a quadruple tracer study with fluorine-18-fluorodeoxyglucose or fluorine-18-fluorodeoxyuridine, L-[methyl-14C]methionine, [6–3H]thymidine, and gallium-67.  J Nucl Med. 1991;  32 2118-2123
• 41 Leyton J, Latigo JR, Perumal M. et al . Early detection of tumor response to chemotherapy by 3’-deoxy-3’-[¹⁸F]fluorothymidine positron emission tomography: the effect of cisplatin on a fibrosarcoma tumor model in vivo.  Cancer Res May. 2005;  65 4202-4210
• 42 Linecker A, Kermer C, Sulzbacher I. et al . Uptake of ¹⁸F-FLT and ¹⁸F-FDG in primary head and neck cancer correlates with survival.  Nuklearmedizin. 2008;  47 80-85
• 43 Lu L, Samuelsson L, Bergstrom M. et al . Rat studies comparing ¹¹C-FMAU, ¹⁸F-FLT, and ⁷⁶Br-BFU as proliferation markers.  J Nucl Med. 2002;  43 1688-1698
• 44 Machulla HJ, Blocher A, Kuntzsch M. et al . Simplified labeling approach for synthesizing 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT).  J Radioanal Nucl Chem. 2000;  24 843-846
• 45 Mangner TJ, Klecker RW, Anderson L. et al . Synthesis of 2’-deoxy-2’-[¹⁸F]fluoro-beta-D-arabinofuranosyl nucleosides [¹⁸F],FAU [¹⁸F],FMAU [¹⁸F],FBAU and [¹⁸F]FIAU, as potential PET agents for imaging cellular proliferation. Synthesis of [¹⁸F]labelled FAU, FMAU, FBAU, FIAU.  Nucl Med Biol. 2003;  30 215-224
• 46 Manning HC, Merchant NB, Foutch AC. et al . Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer.  Clin Cancer Res. 2008;  14 7413-7422
• 47 Martiat P, Ferrant A, Labar D. et al . In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin's lymphoma using positron emission tomography.  J Nucl Med. 1988;  29 1633-1637
• 48 Oyama N, Ponde DE, Dence C. et al . Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation.  J Nucl Med. 2004;  45 519-525
• 49 Perumal M, Pillai RG, Barthel H. et al . Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography.  Cancer Res. 2006;  66 8558-8564
• 50 Pio BS, Park CK, Pietras R. et al . Usefulness of 3’-[¹⁸F]fluoro-3’-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy.  Mol Imaging Biol. 2006;  8 36-42
• 51 Rasey JS, Grierson JR, Wiens LW. et al . Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells.  J Nucl Med. 2002;  43 1210-1217
• 52 Saga T, Kawashima H, Araki N. et al . Evaluation of primary brain tumors with FLT-PET: usefulness and limitations.  Clin Nucl Med. 2006;  31 774-780
• 53 Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle.  J Biol Chem. 1988;  263 8350-8358
• 54 Shields AF, Grierson JR, Dohmen BM. et al . Imaging proliferation in vivo with [¹⁸F]FLT and positron emission tomography.  Nat Med.. 1998;  4 1334-1336
• 55 Shields AF, Lawhorn-Crews JM, Briston DA. et al . Analysis and reproducibility of 3’-Deoxy-3’-[¹⁸F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer.  Clin Cancer Res. 2008;  14 4463-4468
• 56 Shreve P, Anzai Y, Wahl R. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants.  Radiographics. 1999;  19 61-77
• 57 Sohn HJ, Yang YJ, Ryu JS. et al . ¹⁸F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung.  Clin Cancer Res. 2008;  14 7423-7749
• 58 Sugiyama M, Sakahara H, Sato K. et al . Evaluation of 3’-deoxy-3’-¹⁸F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice.  J Nucl Med. 2004;  45 1754-1758
• 59 Tian J, Yang X, Yu L. et al . A multicenter clinical trial on the diagnostic value of dual-tracer PET/CT in pulmonary lesions using 3’-deoxy-3’-¹⁸F-fluorothymidine and ¹⁸F -FDG.  J Nucl Med. 2008;  49 186-194
• 60 Troost EG, Vogel WV, Merkx MA. et al . 18F-FLT PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients.  J Nucl Med. 2007;  48 726-735
• 61 Ullrich R, Backes H, Li H. et al . Glioma proliferation as assessed by 3’-fluoro-3’-deoxy-L-thymidine positron emission tomography in patients with newly diagnosed high-grade glioma.  Clin Cancer Res. 2008;  14 2049-2055
• 62 Borght T van der, Pauwels S, Lambotte L. et al . Brain tumor imaging with PET and 2-[¹¹C]thymidine.  J Nucl Med. 1994;  35 974-982
• 63 Westreenen HL van, Cobben DC, Jager PL. et al . Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer.  J Nucl Med. 2005;  46 400-404
• 64 Vesselle H, Grierson J, Muzi M. 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 3315-3323
• 65 Forstner C von, Egberts JH, Ammerpohl O. et al . Gene expression patterns and tumor uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an orthotopic mouse xenotransplantation model of pancreatic cancer.  J Nucl Med. 2008;  49 1362-1370
• 66 Wagner M, Seitz U, Buck AK. et al . 3’-[¹⁸F]fluoro-3’-deoxythymidine ([¹⁸F]FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease.  Cancer Res. 2003;  63 2681-2687
• 67 Waldherr C, Mellinghoff IK, Tran C. et al . Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3’-deoxy-3’-18F-fluorothymidine PET.  J Nucl Med. 2005;  46 114-120
• 68 Wieder HA, Geinitz H, Rosenberg R. et al . PET imaging with [¹⁸F]3’-deoxy-3’-fluorothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer.  Eur J Nucl Med Mol Imaging. 2007;  34 878-883
• 69 Yamamoto Y, Wong TZ, Turkington TG. et al . 3’-deoxy-3’-[¹⁸F]fluorothymidine positron emission tomography in patients with recurrent glioblastoma multiforme: comparison with Gd-DTPA enhanced magnetic resonance imaging.  Mol Imaging Biol. 2006;  8 340-347
• 70 Yang YJ, Ryu JS, Kim SY. et al . Use of 3’-deoxy-3’-[¹⁸F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors.  Eur J Nucl Med Mol Imaging. 2006;  33 412-419
• 71 Yap CS, Czernin J, Fishbein MC. et al . Evaluation of thoracic tumors with ¹⁸F-fluorothymidine and ¹⁸F-fluorodeoxyglucose-positron emission tomography.  Chest. 2006;  129 393-401

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