Abstract
BackgroundIn a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [18F]flortanidazole ([18F]HX4) small-animal positron emission tomography (μPET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [18F]HX4 as a predictive and/or prognostic biomarker within this setup.MethodsColo205-bearing mice (n = 40) underwent a baseline [18F]HX4 hypoxia μPET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [18F]HX4 was administered intravenously 30 min later, whereupon a second μPET/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[18F]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [18F]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 [18F]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02).ConclusionsMetformin decreased [18F]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [18F]HX4 holds promise as a prognostic imaging biomarker.
Highlights
In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [18F]flortanidazole ([18F]HX4) small-animal positron emission tomography
We demonstrated that [18F]HX4 positron emission tomography (PET) holds potential as a predictive and prognostic imaging biomarker in an A549 non-small cell lung cancer (NSCLC) xenograft model treated with metformin and single-dose radiotherapy [10]
Imaging study Metformin reduces tumor hypoxia in Colo205 tumors In animals treated with metformin 30 min prior to tracer injection, [18F]HX4 to-background ratio (TBR) decreased from 2.53 ± 0.30 at baseline to 2.28 ± 0.26 (p = 0.04; Fig. 2a), but not in the animals treated with saline (2.56 ± 0.39 to 3.08 ± 0.39; p = 0.2; Fig. 2b)
Summary
In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [18F]flortanidazole ([18F]HX4) small-animal positron emission tomography (μPET). An antidiabetic that reduces hepatic gluconeogenesis, has gained significant interest in the oncological field over the last decades This interest in metformin for cancer treatment stems from clinical observations in diabetes patients that metformin use was associated with significantly lower cancer incidence and improved prognosis [1]. The use of metformin as an anticancer therapeutic in non-diabetic cancer patients, including colorectal cancer (CRC) [2, 3], has been tested in different clinical trials, from which the first results are encouraging [2, 4]. Inhibition of the ETC results in a decrease in cellular oxygen consumption and reoxygenation of hypoxic cells [8] This is crucial for radiotherapy to be effective, since the oxygen radicals (as formed by radiation) may inflict damage that is more difficult to repair, as postulated in the ‘oxygen fixation’ hypothesis [11]
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