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Title
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Effects of metformin on tumor hypoxia and radiotherapy efficacy: aHX4 PET imaging study in colorectal cancer xenografts
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Author
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Abstract
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| Background In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [F-18]flortanidazole ([F-18]HX4) small-animal positron emission tomography (mu PET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [F-18]HX4 as a predictive and/or prognostic biomarker within this setup. Methods Colo205-bearing mice (n = 40) underwent a baseline [F-18]HX4 hypoxia mu PET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [F-18]HX4 was administered intravenously 30 min later, whereupon a second mu PET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were further divided into four therapy groups (n = 10/group): control (1), metformin (2), radiotherapy (3), and metformin + radiotherapy, i.e., combination (4). Then, they received a second dose of metformin (groups 2 and 4) or saline (groups 1 and 3), followed by a single radiotherapy dose of 15 Gy (groups 3 and 4) or sham irradiation (groups 1 and 2) 30 min later. Tumor growth was followed three times a week by caliper measurements to assess the therapeutic outcome. Results [F-18]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [F-18]HX4 tumor-to-background ratio (TBR) from 2.53 +/- 0.30 to 2.28 +/- 0.26 (p = 0.04), as opposed to saline treatment (2.56 +/- 0.39 to 3.08 +/- 0.39; p = 0.2). The median tumor doubling time (TDT) was 6, 8, 41, and 43 days in the control, metformin, radiotherapy and combination group, respectively (log-rank p < 0.0001), but no metformin-specific therapy effects could be detected. Baseline [F-18]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02). Conclusions Metformin decreased [F-18]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [F-18]HX4 holds promise as a prognostic imaging biomarker. |
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Language
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English
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Source (journal)
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EJNMMI research. - Heidelberg, 2011, currens
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Publication
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Heidelberg
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Springer Berlin
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2019
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ISSN
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2191-219X
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DOI
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10.1186/S13550-019-0543-4
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Volume/pages
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9
:1
(2019)
, 10 p.
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Article Reference
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74
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ISI
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000480245500001
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Pubmed ID
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31375940
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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