Title
Early prediction of tumor response to treatment : pre-clinical validation of <tex>$^{99m}Tc$</tex>-duramycin Early prediction of tumor response to treatment : pre-clinical validation of <tex>$^{99m}Tc$</tex>-duramycin
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
New York ,
Subject
Human medicine
Source (journal)
The Journal of nuclear medicine. - New York
Volume/pages
(2016) , p. 1-31
ISSN
0161-5505
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/2706ff/132074.pdf
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