Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays. (28th November 2020)

• Record Type: Journal Article
• Authors: Rothkamm, Kai; Christiansen, Sabrina; Rieckmann, Thorsten; Horn, Michael; Frenzel, Thorsten; Brinker, Alexandra; Schumacher, Udo; Stein, Alexander; Petersen, Cordula; Burdak-Rothkamm, Susanne
• Is Part Of: Cancer letters. Volume 493(2020)
• Page Start: 179
• Page End: 188
• Publication Date: 2020-11-28
• Subjects: Trifluridine -- TAS-102 -- Colorectal cancer -- Chemoradiation -- Radiotherapy; 5-FU 5-fluorouracil -- FTD trifluridine -- CI confidence interval -- EdU 5-ethynyl-2′-deoxyuridine -- HR hazard ratio -- mCRC metastatic colorectal cancer -- RT radiotherapy -- T/C treated vs. control ratio -- TPI tipiracil; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.08.038
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf®) has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Here we investigated the colorectal cancer cell lines HT29, HCT116, SW48 and Caco-2 to provide a preclinical rationale for FTD/TPI-based chemoradiation treatment. All lines incorporated similar amounts of FTD, irrespective of treatment concentration and duration, then arrested in S phase, showed persistent γH2AX induction and eventually underwent endoreplication, resulting in polyploidy. Clonogenic assays performed for four combined treatment schedules demonstrated additivity for treatments given within 6 h of each other. However, 24 h FTD/TPI treatment prior to irradiation caused 1.6–2.4 fold radiosensitisation. Combined in vivo treatment was well tolerated and caused a marked tumour growth delay, similar to capecitabine radiochemotherapy regimes. Prolonged S phase arrest, persistent γH2AX signalling, endoreplication and polyploidy may contribute to the cytotoxicity of FTD/TPI. The strong radiosensitising effect observed in vitro after prolonged treatment with FTD/TPI and equivalence with capecitabine-based chemoradiation in vivo support a daily fractionated combined regime of FTD/TPI and radiation in rectal cancer treatment. This is now being tested in a phase I/II clinical trial (NCT04177602). Highlights: Trifluridine is incorporated into cancer cell nuclei and induces gamma-H2AX, a marker of DNA damage, in S/G2 phase cells. Cancer cells undergo endoreduplication and become polyploid after prolonged trifluridine/tipiracil treatment. Prolonged, but not short treatment with trifluridine/tipiracil radiosensitises cancer cells. Trifluridine- and capecitabine-based chemoradiation cause a similar tumour growth delay in three colorectal cancer xenografts.