Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice: comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose (FDG) and 3'-[18F]fluoro-3'-deoxythymidine (FLT)

Carla F M Molthoff, Bianca M Klabbers, Johannes Berkhof, Jasper T Felten, Marcelle van Gelder, Albert D Windhorst, Ben J Slotman, Adriaan A Lammertsma, Carla F M Molthoff, Bianca M Klabbers, Johannes Berkhof, Jasper T Felten, Marcelle van Gelder, Albert D Windhorst, Ben J Slotman, Adriaan A Lammertsma

Abstract

Objective: The uptake of 3'-[18F]fluoro-3'-deoxythymidine (FLT), a proliferation marker, was measured before and during fractionated radiotherapy to evaluate the potential of FLT-positron emission tomography (PET) imaging as an indicator of tumor response compared to 2'-deoxy-2'-[18F]fluoro-D-glucose (FDG).

Materials and methods: Nude mice bearing established human head and neck xenografts (HNX-OE; nu/nu mice) were locally irradiated (three fractions/week; 22 Gy) using a 150-kVp unit. Multiple FDG- and FLT-PET scans were acquired during treatment. Tumor volume was determined regularly, and tissue was analyzed for biomarkers involved in tracer uptake.

Results: Both groups revealed a significant decline in tumor volume (P<0.01) compared to untreated tumors. For FDG as well as for FLT, a significant decline in retention was observed at day 4. For FLT, most significant decline in retention was observed at day 12; whereas, for FDG, this was already noted at day 4. Maximum decline in tumor-to-nontumor ratios (T/NT) for FDG and FLT was 42+/-18% and 49+/-16% (mean+/-SD), respectively. FLT uptake was higher then that of FDG. For FLT, statistical significant correlations were found for both tumor volume at baseline and at day 29 with T/NT and DeltaT/NT. All tumors demonstrated expression of glucose transporter-1, thymidine kinase-1, and hexokinase II. No differences were found for amount of tumor cells and necrosis at the end of treatment.

Conclusion: This new experimental in vivo model supports the promise of using FLT-PET, as with FDG-PET, to monitor response to external radiotherapy. This warrants further clinical studies to compare these two tracers especially in cancers treated with radiotherapy.

Figures

Fig. 1
Fig. 1
Tumor growth of HNX-OE xenografts relative to tumor volume at start of local radiotherapy.
Fig. 2
Fig. 2
Tumor growth of HNX-OE xenografts relative to tumor volume at start of local radiotherapy in controls and FDG and FLT groups.
Fig. 3
Fig. 3
FDG and FLT accumulation in HNX-OE xenografts. a absolute T/NT, tumor-to-nontumor ratio; b relative T/NT, tumor-to-nontumor ratio

References

    1. None
    2. Lowe VL SJB (2003) PET imaging head and neck cancer. In: Valk PE, Bailey DL, Townsend DW, Maisey MN (eds) Positron emission tomography. London: Springer
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/ijc.20379', 'is_inner': False, 'url': 'https://doi.org/10.1002/ijc.20379'}, {'type': 'PubMed', 'value': '15382034', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15382034/'}]}
    2. Kim MM, Califano JA (2004) Molecular pathology of head-and-neck cancer. Int J Cancer 112:545–553
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1001/archotol.130.12.1361', 'is_inner': False, 'url': 'https://doi.org/10.1001/archotol.130.12.1361'}, {'type': 'PubMed', 'value': '15611393', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15611393/'}]}
    2. Schwartz DL, Rajendran J, Yueh B, et al. (2004) FDG-PET prediction of head and neck squamous cell cancer outcomes. Arch Otolaryngol Head Neck Surg 130:1361–1367
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s00405-003-0581-3', 'is_inner': False, 'url': 'https://doi.org/10.1007/s00405-003-0581-3'}, {'type': 'PubMed', 'value': '12736744', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12736744/'}]}
    2. Hardisson D (2003) Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 260:502–508
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S1536-1632(03)00102-1', 'is_inner': False, 'url': 'https://doi.org/10.1016/s1536-1632(03)00102-1'}, {'type': 'PubMed', 'value': '14499141', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14499141/'}]}
    2. Klabbers BM, Lammertsma AA, Slotman BJ (2003) The value of positron emission tomography for monitoring response to radiotherapy in head and neck cancer. Mol Imag Biol 5:257–270
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/PL00008465', 'is_inner': False, 'url': 'https://doi.org/10.1007/pl00008465'}, {'type': 'PubMed', 'value': '11043392', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11043392/'}]}
    2. Pauwels EK, Sturm EJ, Bombardieri E, Cleton FJ, Stokkel MP (2000) Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies. J Cancer Res Clin Oncol 126:549–559
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15001687', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15001687/'}]}
    2. Maschauer S, Prante O, Hoffmann M, Deichen JT, Kuwert T (2004) Characterization of 18F-FDG uptake in human endothelial cells in vitro. J Nucl Med 45(3):455–460
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9490094', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9490094/'}]}
    2. Brun E, Ohlsson T, Erlandsson K, et al. (1997) Early prediction of treatment outcome in head and neck cancer with 2-18FDG PET. Acta Oncol 36(7):741–747
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9293793', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9293793/'}]}
    2. Hautzel H, Muller-Gartner HW (1997) Early changes in fluorine-18-FDG uptake during radiotherapy. J Nucl Med 38:1384–1386
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '1432158', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/1432158/'}]}
    2. Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T (1992) Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 33:1972–1980
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '11535734', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11535734/'}]}
    2. Zhuang H, Pourdehnad M, Lambright ES, et al. (2001) Dual time point 18F-FDG PET imaging for differentiating malignant from inflammatory processes. J Nucl Med 42:1412–1417
    1. None
    2. Direcks WGE, Lammertsma AA, Molthoff CF (2006) 3′-Deoxy-3′-18F-Fluorothymidine as a tracer of proliferation in positron emission tomography. In: GJ Peters (ed) Cancer drug discovery and development, deoxynucleoside analogs in cancer therapy. Totowa, NJ, USA: Humana Press Inc., pp 441–462
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/3337', 'is_inner': False, 'url': 'https://doi.org/10.1038/3337'}, {'type': 'PubMed', 'value': '9809561', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9809561/'}]}
    2. Shields AF, Grierson JR, Dohmen BM, et al. (1998) Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4:1334–1336
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12429617', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12429617/'}]}
    2. Vesselle H, Grierson J, Muzi M, et al. (2002) 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 Cancer Res 8:3315–3323
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/0163-7258(95)00015-9', 'is_inner': False, 'url': 'https://doi.org/10.1016/0163-7258(95)00015-9'}, {'type': 'PubMed', 'value': '7494863', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/7494863/'}]}
    2. Arner ES, Eriksson S (1995) Mammalian deoxyribonucleoside kinases. Pharmacol Ther 67:155–186
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s00259-004-1611-0', 'is_inner': False, 'url': 'https://doi.org/10.1007/s00259-004-1611-0'}, {'type': 'PubMed', 'value': '15791434', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15791434/'}]}
    2. Barthel H, Perumal M, Latigo J, et al. (2005) 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 32:257–263
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.nucmedbio.2004.06.004', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.nucmedbio.2004.06.004'}, {'type': 'PubMed', 'value': '15464384', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15464384/'}]}
    2. Grierson JR, Schwartz JL, Muzi M, Jordan R, Krohn KA (2004) Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. Nucl Med Biol 31:829–837
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12215561', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12215561/'}]}
    2. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL (2002) Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 43:1210–1217
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12960188', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12960188/'}]}
    2. Shields AF (2003) PET imaging with 18F-FLT and thymidine analogs: promise and pitfalls. J Nucl Med 44:1432–1434
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15750150', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15750150/'}]}
    2. van Westreenen HL, Cobben DC, Jager PL, et al. (2005) Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. J Nucl Med 46:400–404
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15073267', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15073267/'}]}
    2. van Waarde A, Cobben DC, Suurmeijer AJ, et al. (2004) Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med 45(4):695–700
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/1097-0215(20010601)92:5<661::AID-IJC1251>3.0.CO;2-O', 'is_inner': False, 'url': 'https://doi.org/10.1002/1097-0215(20010601)92:5<661::aid-ijc1251>3.0.co;2-o'}, {'type': 'PubMed', 'value': '11340568', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11340568/'}]}
    2. Klaassen I, Brakenhoff RH, Smeets SJ, Snow GB, Braakhuis BJ (2001) Expression of retinoic acid receptor gamma correlates with retinoic acid sensitivity and metabolism in head and neck squamous cell carcinoma cell lines. Int J Cancer 92:661–665
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/(SICI)1097-0215(19970502)71:3<410::AID-IJC18>3.0.CO;2-J', 'is_inner': False, 'url': 'https://doi.org/10.1002/(sici)1097-0215(19970502)71:3<410::aid-ijc18>3.0.co;2-j'}, {'type': 'PubMed', 'value': '9139877', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9139877/'}]}
    2. Welters MJ, Fichtinger-Schepman AM, Baan RA, et al. (1997) Relationship between the parameters cellular differentiation, doubling time and platinum accumulation and cisplatin sensitivity in a panel of head and neck cancer cell lines. Int J Cancer 71:410–415
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/ijc.2910470114', 'is_inner': False, 'url': 'https://doi.org/10.1002/ijc.2910470114'}, {'type': 'PubMed', 'value': '1985883', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/1985883/'}]}
    2. Molthoff CF, Calame JJ, Pinedo HM, Boven E (1991) Human ovarian cancer xenografts in nude mice: characterization and analysis of antigen expression. Int J Cancer 47:72–79
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '2979771', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/2979771/'}]}
    2. Peters GJ, Van Dijk J, Nadal JC, Van Groeningen CJ, Lankelma J, Pinedo HM (1987) Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer. in vivo 1:113–117
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/BF00300234', 'is_inner': False, 'url': 'https://doi.org/10.1007/bf00300234'}, {'type': 'PubMed', 'value': '2544306', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/2544306/'}]}
    2. Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24:148–154
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1023/A:1010684101509', 'is_inner': False, 'url': 'https://doi.org/10.1023/a:1010684101509'}]}
    2. Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson JR (2000) Simplified labeling approach for synthesizing 3′-deoxy-3′-[F-18]fluorothymidine ([F-18]FLT). J Radioanal Nucl Chem 243:843–846
    1. None
    2. de Jong H, Knoess C, Lammertsma AA, et al. (2004) Performance characteristics of the high resolution research tomograph comparison of three prototypes. IEEE Med Imaging Conf Record 6:3437–3439
    1. van der Veldt AA, Hooft L, van Diest PJ, et al. (2006) Microvessel density and p53 in detecting cervical cancer by FDG PET in cases of suspected recurrence. Eur J Nucl Med Mol Imaging 33:1408–1416
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1200/JCO.20.2.379', 'is_inner': False, 'url': 'https://doi.org/10.1200/jco.20.2.379'}, {'type': 'PubMed', 'value': '11786564', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11786564/'}]}
    2. Bos R, van der Hoeven JJM, van der Wall E, et al. (2002) Biologic correlates of 18Fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 20:379–387
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1210/jc.2004-0779', 'is_inner': False, 'url': 'https://doi.org/10.1210/jc.2004-0779'}, {'type': 'PubMed', 'value': '15509640', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15509640/'}]}
    2. Hooft L, van der Veldt AA, van Diest PJ, et al. (2005) [18F]fluorodeoxyglucose uptake in recurrent thyroid cancer is related to hexokinase i expression in the primary tumor. J Clin Endocrinol Metab 90:328–334
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '10690556', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10690556/'}]}
    2. Milas L, Mason K, Hunter N, et al. (2000) in vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6:701–708
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s004320050351', 'is_inner': False, 'url': 'https://doi.org/10.1007/s004320050351'}, {'type': 'PubMed', 'value': '10870642', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10870642/'}]}
    2. Jackel MC, Kopf-Maier P, Baumgart F, Ziessow D, Tausch-Treml R (2000) Value of 31P NMR spectroscopy in predicting the response of a xenografted human hypopharynx carcinoma to irradiation. J Cancer Res Clin Oncol 126:325–331
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12571214', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12571214/'}]}
    2. Kostakoglu L, Goldsmith SJ (2003) 18F-FDG PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma. J Nucl Med 44:224–239
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15471845', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15471845/'}]}
    2. Sugiyama M, Sakahara H, Sato K, et al. (2004) Evaluation of 3′-deoxy-3′-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. J Nucl Med 45:1754–1758
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '14960640', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14960640/'}]}
    2. Cobben DC, van der Laan BF, Maas B, et al. (2004) 18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET. J Nucl Med 45:226–231
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s00259-004-1462-8', 'is_inner': False, 'url': 'https://doi.org/10.1007/s00259-004-1462-8'}, {'type': 'PubMed', 'value': '14991243', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14991243/'}]}
    2. Smyczek-Gargya B, Fersis N, Dittmann H, et al. (2004) PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging 31:720–724
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '14734681', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14734681/'}]}
    2. Dearling JL, Flynn AA, Sutcliffe-Goulden J, et al. (2004) Analysis of the regional uptake of radiolabeled deoxyglucose analogs in human tumor xenografts. J Nucl Med 45:101–107
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S1095-0397(99)00031-X', 'is_inner': False, 'url': 'https://doi.org/10.1016/s1095-0397(99)00031-x'}, {'type': 'PubMed', 'value': '14516653', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14516653/'}]}
    2. Humm JL, Lee J, O’Donoghue JA, et al. (1999) Changes in FDG tumor uptake during and after fractionated radiation therapy in a rodent tumor xenograft. Clin Positron Imaging 2:289–296
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1080/095530099139764', 'is_inner': False, 'url': 'https://doi.org/10.1080/095530099139764'}, {'type': 'PubMed', 'value': '10465366', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10465366/'}]}
    2. Wei S, Ageron-Blanc A, Petridis F, Beaumatin J, Bonnet S, Luccioni C (1999) Radiation-induced changes in nucleotide metabolism of two colon cancer cell lines with different radiosensitivities. Int J Radiat Biol 75:1005–1013
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1080/09553009014551461', 'is_inner': False, 'url': 'https://doi.org/10.1080/09553009014551461'}, {'type': 'PubMed', 'value': '1973443', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/1973443/'}]}
    2. Hohn-Elkarim K, Muhlensiepen H, Altman KI, Feinendegen LE (1990) Modification of effects of radiation on thymidine kinase. Int J Radiat Biol 58:97–110

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