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Title
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Early prediction of tumor response to treatment : pre-clinical validation of -duramycin
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Author
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Abstract
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| Non-invasive imaging of cell death can provide an early indication of tumor treatment efficacy which will aid clinicians to timely distinguish responding versus non-responding patients. 99mTc-duramycin is a SPECT tracer for cell death imaging. In this study, we aimed at validating 99mTc-duramycin for imaging early tumor treatment response. Methods: An in vitro binding assay was performed in COLO205 cells treated with 5-FU (3.1, 31 or 310 µM) and oxaliplatin (0.7 or 7 µM) or radiation (2 or 4.5 Gy). 99mTc-duramycin cell binding and the levels of cell death were evaluated after treatment. In vivo imaging was performed in CD1-/- mice bearing COLO205 human colorectal cancer tumors treated with irinotecan (100 mg/kg), oxaliplatin (5 mg/kg), irinotecan (80 mg/kg) in combination with oxaliplatin (5 mg/kg) or vehicle (0.9% NaCl and 5% glucose; n = 6/group). For radiotherapy studies, COLO205 tumors received 4.5 Gy, two fractions of 4.5 Gy in a 24 h interval, pre-treatment with 80 mg/kg irinotecan combined with two fractions of 4.5 Gy in a 24 h interval or no treatment (n = 5-6/group). Therapy response was evaluated by 99mTc duramycin SPECT 24 h after the last dose of therapy. Blocking was used to confirm tracer specificity. Radiotracer uptake in the tumors was validated ex vivo using γ-counting, cleaved caspase-3 and TUNEL histology. Results: Chemo- and radiotherapy treatment increased 99mTc-duramycin binding to COLO205 cells in a concentration/dose- and time-dependent manner, which was in good correlation with cell death levels (p<0.05) as analyzed by annexin V and caspase 3/7 activity. In vivo, 99mTc-duramycin uptake in COLO205 xenografts was increased 2.3- and 2.8-fold (p<0.001), in mice treated with irinotecan and combination therapy, respectively. Blocking with unlabeled duramycin demonstrated specific binding of the radiotracer. After tumor irradiation with 4.5 Gy, 99mTc-duramycin uptake in tumors increased significantly (1.24 ± 0.07%I.D./g vs. 0.57 ± 0.08%I.D./g in the unirradiated tumors; p<0.001). Gamma-counting of radioactivity in the tumors positively correlated with cleaved caspase-3 (r=0.85, p<0.001) and TUNEL (r=0.81, p<0.001) staining. Conclusion: We demonstrated that 99mTc-duramycin can be used to image cell death induction early after chemotherapy and radiotherapy. It holds potential to be translated into clinical assessment of early treatment response. |
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Language
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English
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Source (journal)
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The Journal of nuclear medicine. - New York
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Publication
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New York
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2016
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ISSN
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0161-5505
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DOI
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10.2967/JNUMED.115.168344
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Volume/pages
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57
:5
(2016)
, p. 805-811
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ISI
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000375372700054
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Full text (Publisher's DOI)
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Full text (open access)
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