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. 2018 Sep 21;8:14191. doi: 10.1038/s41598-018-32578-w

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Increased survival of NOD-SCID mice bearing orthotopic adult COMI GB treated by KU60019 plus RT. At d41 of tumor development, animals were i.c.-injected by CED with 12.5 µl of 250 µM KU60019 (blue) or vehicle (ethanol in 0.9% NaCl - black) followed by irradiation with 2.5 Gy to the head at d45, 46 and 48 (total dose delivered: 7.5 Gy). (A) Kaplan-Meier survival curves. Median survival of KU60019-treated animals was significantly longer than that of vehicle-treated controls (101 vs 91 days; ratio: 0.901; 95% CI of ratio: 0.5384 to 1.264; P: 0.0409 indicated by one asterisk). (B) H/E staining of tumors at euthanasia (d91 and 104 in vehicle and KU60019-injected mice, respectively). Mouse ID numbers 22.1 and 22.15 are indicated for the sake of reference. Left: 2X snap photographs. Right: 100X magnifications showing tumor infiltrating cells. (C) 3 T MRI of orthotopic tumors carried out at d62. Top: tumors treated with vehicle+ (2.5 Gy × 3). Bottom: tumors treated with KU60019+ (2.5 Gy × 3). Mouse ID numbers are indicated for the sake of reference. (D) Determination of tumor volumes by region segmentation software (GRES). Top: example of segmented tumor. The mouse ID number (22.14) is indicated for the sake of reference. Bottom: mean ± SEM volumes of vehicle + (2.5 Gy × 3) (black) and KU60019+ (2.5 Gy × 3) (blue) – treated tumors. The tumor volumes in KU60019+ (2.5 Gy × 3) – treated mice were significantly reduced as compared to vehicle + (2.5 Gy × 3) -treated mice. Mean ± SEM of vehicle+ (2.5 Gy × 3): 140 ± 17 mm³; mean ± SEM of KU60019+ (2.5 Gy × 3): 97 ± 11 mm³; P: 0.047 after two-tailed unpaired t-test. (E) Further beneficial effect on animal survival after RT hyperfractionation. At d16 of tumor development, animals were i.c.-injected by CED in the surgery room with 12.5 µl of 250 µM KU60019 (blue) or vehicle (ethanol in 0.9% NaCl - black) followed by irradiation with 15 fractions of 0.5 Gy IR delivered to the head of mice 2–4 days apart (total dose delivered: 7.5 Gy). Kaplan-Meier survival curves are shown. Median survival of KU60019-treated animals was further increased (105 vs 89 days; ratio: 0.847; 95% CI of ratio: 0.4969 to 1.198; P: 0.0417) with respect to controls as compared to standard 2.5 Gy fractions as shown in A.