The differential diagnosis between brain tumors recurrence and early neuroinflammation or late radionecrosis is still an unsolved problem. The new emerging magnetic resonance imaging, computed tomography, and positron emission tomography diagnostic modalities still lack sufficient accuracy. In the last years, a great effort has been made to develop radiotracers able to detect specific altered metabolic pathways or tumor receptor markers. Our research project aims to evaluate irradiation effects on radiopharmaceutical uptake and compare the kinetic of the fluorinate tracers. T98G glioblastoma cells were irradiated at doses of 2, 10, and 20 Gy with photons, and 18F-DOPA and 18F-FET tracer uptake was evaluated. Activity and cell viability at different incubation times were measured. 18F-FET and 18F-DOPA are accumulated via the LAT-1 transporter, but 18F-DOPA is further incorporated, whereas 18F-FET is not metabolized. Therefore, time-activity curves (TACs) tend to plateau with 18F-DOPA and to a rapid washout with 18F-FET. After irradiation, 18F-DOPA TAC resembles the 18F-FET pattern. 18F-DOPA activity peak we observed at 20 min might be fictitious, because earlier time points have not been evaluated, and a higher activity peak before 20 min cannot be excluded. In addition, the activity retained in the irradiated cells remains higher in comparison to the sham ones at all time points investigated. This aspect is similar in the 18F-FET TAC but less evident. Therefore, we can hypothesize the presence of a second intracellular compartment in addition to the amino acidic pool one governed by LAT-1, which could explain the progressive accumulation of 18F-DOPA in unirradiated cells.

CNAO National Centre for Oncological Hadrontherapy Pavia Italy

Department of Biology and Biotechnology Lazzaro Spallanzani University of Pavia Pavia Italy

Nuclear Medicine Department Faculty of Medicine and Dentistry Palackı University Olomouc Olomouc Czechia

Nuclear Medicine Research Department IASON Graz Austria

Nuclear Medicine Unit Fondazione IRCCS Policlinico San Matteo Pavia Italy

Oncology Unit Fondazione IRCCS Policlinico San Matteo Pavia Italy

University School for Advanced Studies IUSS Pavia Pavia Italy

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Adamopoulos P. G., Tsiakanikas P., Kontos C. K., Panagiotou A., Vassilacopoulou D., Scorilas A. (2019). Identification of novel alternative splice variants of the human L-DOPA decarboxylase (DDC) gene in human cancer cells, using high-throughput sequencing approaches. Gene 719:144075. 10.1016/j.gene.2019.144075 PubMed DOI

Alexiou G., Vartholomatos E., Tsamis K., Peponi E., Markopoulos G., Papathanasopoulou V. A., et al. (2019). Combination treatment for glioblastoma with temozolomide. DFMO and radiation. J. BUON 24 397–404. PubMed

Bleeker F. E., Lamba S., Leenstra S., Troost D., Hulsebos T., Vandertop W. P., et al. (2009). IDH1R132 mutations occur frequently in high-grade gliomas but not in other solid tumors. Hum. Mutation 30 7–1. 10.1002/humu.20937 PubMed DOI

Buroni F. E., Pasi F., Persico M. G., Lodola L., Aprile C., Nano R. (2015). Evidence of 18F-FCH uptake in human T98G glioblastoma cells. Anticancer Res. 35 6439–6444. PubMed

Carlsson S. K., Brothers S. P., Wahlestedt C. (2014). Emerging treatment strategies for glioblastoma multiforme. EMBO Mol. Med. 6 1359–1370. 10.15252/emmm.201302627 PubMed DOI PMC

Chalatsa I., Nikolouzou E., Vassilacopoulou D. (2011). L-Dopa decarboxylase expression profile in human cancer cells. Mol. Biol. Rep. 38 1005–1011. 10.1007/s11033-010-0196-x PubMed DOI

Chan S. W., Dunlop R. A., Rowe A., Double K. L., Rodgers K. J. (2012). L-DOPA is incorporated into brain proteins of patients treated for Parkinson’s disease, inducing toxicity in human neuroblastoma cells in vitro. Exp. Neurol. 238 29–37. 10.1016/j.expneurol.2011.09.029 PubMed DOI

Cheon G. J., Chung H. K., Lee S. J., Ahn S. H., Lee T. S., Choi C. W. (2007). Cellular metabolic responses of PET radiotracers to (188)Re radiation in an MCF7 cell line containing dominant-negative mutant p53. Nucl. Med. Biol. 34 425–432. 10.1016/j.nucmedbio.2007.01.011 PubMed DOI

Chiaravalloti A., Fiorentini A., Villani V., Carapella C., Pace A., Di Pietro B., et al. (2015). Factors affecting (1)(8)F-FDOPA standardized uptake value in patients with primary brain tumors after treatment. Nucl. Med. Biol. 42 355–359. 10.1016/j.nucmedbio.2015.01.002 PubMed DOI

Chopra A. (2007). [18F]6-fluoro-3-O-methyl-L-3,4-dihydroxyphenylalanine. Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda, MD: National Center for Biotechnology Information.

Dadone-Montaudié B., Ambrosetti D., Dufour M., Darcourt J., Almairac F., Coyne J., et al. (2017). [18F] FDOPA standardized uptake values of brain tumors are not exclusively dependent on LAT1 expression. PLoS One 22:e0184625. 10.1371/journal.pone.0184625 PubMed DOI PMC

Daidone F., Montioli R., Paiardini A., Cellini B., Macchiarulo A., Giardina G., et al. (2012). Identification by Virtual Screening and In Vitro Testing of Human DOPA Decarboxylase Inhibitors. PLoS One 7:e31610. 10.1371/journal.pone.0031610 PubMed DOI PMC

Frosina G. (2016). Positron emission tomography of high-grade gliomas. J. Neurooncol. 127 415–425. 10.1007/s11060-016-2077-1 PubMed DOI

Functional Annotation of the Mammalian Genome (2012). Functional Annotation of the Mammalian Genome. Available Online at: https://fantom.gsc.riken.jp/5/sstar/EntrezGene:1644 (accessed July 30, 2020).

Galldiks N., Stoffels G., Filss C. P., Piroth M. D., Sabel M., Ruge M. I. (2012). Role of O-(2-18F-Fluoroethyl)-L-tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis. J. Nucl. Med. 53 1367–1374. 10.2967/jnumed.112.103325 PubMed DOI

Gazdar A. F., Helman L. J., Israel M. A., Russell E. K., Linnoila R. I., Mulshine J. L., et al. (1988). Expression of neuroendocrine cell markers L-dopa decarboxylase, chromogranin A, and dense core granules in human tumors of endocrine and nonendocrine origin. Cancer Res. 48 4078–4082. PubMed

Gilbert M. R. (2011). Recurrent glioblastoma: a fresh look at current therapies and emerging novel approaches. Semin. Oncol. 38(Suppl. 4), S21–S33. PubMed

Ginet M., Zaragori T., Marie P. Y., Roch V., Gauchotte G., Rech F., et al. (2020). Integration of dynamic parameters in the analysis of 18 F-FDopa PET imaging improves the prediction of molecular features of gliomas. Eur. J. Nucl. Med. Mol. Imaging 47 1381–1390. 10.1007/s00259-019-04509-y PubMed DOI

Graves A., Win T., Haim S. B., Ell P. J. (2007). Non-[18F]FDG PET in clinical oncology. Lancet Oncol. 8 822–830. 10.1016/s1470-2045(07)70274-7 PubMed DOI

Haase C., Bergmann R., Fuechtner F., Hoepping A., Pietzsch J. (2007). L-type amino acid transporters LAT1 and LAT4 in cancer: uptake of 3-O-methyl-6-18F-fluoro-L-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo. J. Nucl. Med. 48 2063–2071. 10.2967/jnumed.107.043620 PubMed DOI

Habermeier A., Graf J., Sandhofer B. F., Boissel J. P., Roesch F., Closs I. (2015). System l amino acid transporter LAT1 accumulates O-(2-fluoroethyl)-l-tyrosine (FET). Amino Acids 47 335–344. 10.1007/s00726-014-1863-3 PubMed DOI

Heiss W. D., Wienhard K., Wagner R., Lanfermann H., Thiel A., Herholz K., et al. (1996). F-Dopa as an Amino acid tracer to detect brain Tumors. J. Nucl. Med. 37 1180–1182. PubMed

Ichimura K., Pearson D. M., Kocialkowski S., Backlund L. M., Chan R., Collins V. P. (2009). IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-oncol. 11 341–347. 10.1215/15228517-2009-025 PubMed DOI PMC

Langen K. J., Stoffels G., Fliss C., Heinzel A., Stegmayr C., Lohmann P. (2017). Imaging of amino acid transport in brain tumours: Positron emission tomography with O-(2-[18F]fluoroethyl)-L-tyrosine (FET). Methods 130 124–134. 10.1016/j.ymeth.2017.05.019 PubMed DOI

Lee S. Y., Jeong E. K., Ju M. K., Jeon H. M., Kim M. Y., Kim C. H., et al. (2017). Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol. Cancer 16:10. 10.1186/s12943-016-0577-4 PubMed DOI PMC

Murad H., Alghamian Y., Aljapawe A., Madania A. (2018). Effects of ionizing radiation on the viability and proliferative behavior of the human glioblastoma T98G cell line. BMC Res. Notes 11:330. 10.1186/s13104-018-3438-y PubMed DOI PMC

Nanni C., Fantini L., Nicolini S., Fanti S. (2010). Non FDG PET. Clin. Radiol. 65 536–548. PubMed

Paget V., Kacem M. B., Dos Santos M., Benadjaoud M. A., Soysouvanh F., Buard V., et al. (2019). Multiparametric radiobiological assays show that variation of X-ray energy strongly impacts relative biological effectiveness: comparison between 220 kV and 4 MV. Sci. Rep. 9:14328. 10.1038/s41598-019-50908-4 PubMed DOI PMC

Pasi F., Persico M. G., Buroni F. E., Aprile C., Hodoliè M., Corbella F., et al. (2017). Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions. Contr. Media Mol. Imaging 16:6491674. 10.1515/raon-2016-0022 PubMed DOI PMC

Patsis C., Glyka V., Yiotakis I., Fragoulis E. G., Scorilas A. (2012). l-DOPA Decarboxylase (DDC) Expression Status as a Novel Molecular Tumor Marker for Diagnostic and Prognostic Purposes in Laryngeal Cancer. Transl. Oncol. 5 288–296. 10.1593/tlo.12223 PubMed DOI PMC

Petrujkiæa K., Miloševiæc N., Rajkoviæ N. (2019). Computational quantitative MR image features - a potential useful tool in differentiating glioblastoma from solitary brain metastasis. Eur. J. Radiol. 119:108634. 10.1016/j.ejrad.2019.08.003 PubMed DOI

Rodgers K. J., Hume P. M., Morris J. G., Dean R. T. (2006). Evidence for L-dopa incorporation into cell proteins in patients treated with levodopa. J. Neurochem. 98 1061–1070. 10.1111/j.1471-4159.2006.03941.x PubMed DOI

Schiepers C., Chen W., Cloughesy T., Dahlbom M., Huang S. C. (2007). 18F-FDOPA kinetics in brain tumors. J. Nucl. Med. 48 1651–1661. 10.2967/jnumed.106.039321 PubMed DOI

Schmidt J. A., Rinaldi S., Scalbert A., Ferrari P., Achaintre D., Gunter M. J., et al. (2016). Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur. J. Clin. Nutrition 70 306–312. 10.1038/ejcn.2015.144 PubMed DOI PMC

Spaeth N., Wyss M. T., Pahnke J., Biollaz G., Lutz A., Goepfert K. (2006). Uptake of 18F-fluorocholine, 18Ffluoro-ethyl L-tyrosine and 18F-fluoro-2-deoxyglucose in F98 gliomas in the rat. Eur. J. Nucl. Med. Mol. Imaging 33 673–682. 10.1007/s00259-005-0045-7 PubMed DOI

Stadlbauer A., Prante O., Nimsky C., Alomonowitz E., Buchfelder M., Kuwert T. (2008). Metabolic Imaging of Cerebral Gliomas: Spatial Correlation of Changes in O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Proton Magnetic Resonance Spectroscopic Imaging. J. Nucl. Med. 49 721–729. 10.2967/jnumed.107.049213 PubMed DOI

Van Meir E. G., Kikuchi T., Tada M., Li H., Diserens A. C., Wojcik B. E., et al. (1994). Analysis of the p53 Gene and Its Expression in Human Glioblastoma Cells. Cancer Res. 54 649–652. PubMed

Wardak M., Schiepers C., Cloughesy T. F., Dahlbom M., Phelps M. E., Huang S. C. (2014). 18F-FLT and 18F-FDOPA PET Kinetics in Recurrent Brain Tumors. Eur. J. Nucl. Med. Mol. Imaging 41 1199–1209. 10.1007/s00259-013-2678-2 PubMed DOI PMC

Youland R. S., Kitange G. J., Peterson T. E., Pafundi D. H., Ramiscal J. A., Pokorny J. L., et al. (2013). The role of LAT1 in (18)F-DOPA uptake in malignant gliomas. J. Neurooncol. 111 11–18. 10.1007/s11060-012-0986-1 PubMed DOI PMC