Journal
CANCER LETTERS
Volume 493, Issue -, Pages 179-188Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.08.038
Keywords
Trifluridine; TAS-102; Colorectal cancer; Chemoradiation; Radiotherapy
Categories
Funding
- Servier Affaires Medicales
- Mildred-Scheel Cancer Career Center Hamburg
- Servier Deutschland GmbH
- German Cancer Aid
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Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf (R)) 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 gamma H2AX 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 gamma H2AX 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).
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