Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Does Timing Matter in Radiotherapy of Hepatocellular Carcinoma?

Soha Hassan
ORCID logo ,
Amira Ali
ORCID logo ,
Dennis Sohn
,
Uli Floegel
,
Reiner Jaenicke
,
Horst Werner Korf
* ORCID logo ,
Charlotte von Gall
Version 1 : Received: 28 January 2021 / Approved: 29 January 2021 / Online: 29 January 2021 (08:15:35 CET)

How to cite: Hassan, S.; Ali, A.; Sohn, D.; Floegel, U.; Jaenicke, R.; Korf, H.W.; von Gall, C. Does Timing Matter in Radiotherapy of Hepatocellular Carcinoma?. Preprints 2021, 2021010603. https://doi.org/10.20944/preprints202101.0603.v1 Hassan, S.; Ali, A.; Sohn, D.; Floegel, U.; Jaenicke, R.; Korf, H.W.; von Gall, C. Does Timing Matter in Radiotherapy of Hepatocellular Carcinoma?. Preprints 2021, 2021010603. https://doi.org/10.20944/preprints202101.0603.v1

Abstract

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

Keywords

Clock genes; Hepatocellular carcinoma; Ki67; Radiotherapy; Transgenic Per2::luc mice; γ-H2AX

Subject

Medicine and Pharmacology, Immunology and Allergy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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