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).

在大肠癌中，氟嘧啶失败后，三氟吡啶/替普拉西酯（FTD / TPI；以Lonsurf®出售）已显示出与临床相关的活性，因此与目前的标准卡培他滨化学放疗相比，其功效可能更高。在这里，我们研究了结直肠癌细胞系HT29，HCT116，SW48和Caco-2，以提供基于FTD / TPI的化学放射治疗的临床前原理。

不论处理浓度和持续时间如何，所有掺入相似量的FTD的品系，然后停在S期，表现出持续的γH2AX诱导作用，最终进行内复制，从而形成多倍体。对四个组合治疗方案进行的克隆试验表明彼此在6小时内给予的治疗具有可加性。但是，辐照前24小时FTD / TPI处理导致放射敏化度为1.6-2.4倍。与卡培他滨放射化疗方案相似，体内联合治疗耐受性良好，并引起明显的肿瘤生长延迟。

延长的S期停滞，持续的γH2AX信号传导，内向复制和多倍体可能有助于FTD / TPI的细胞毒性。在长时间使用FTD / TPI进行治疗以及体内等效于基于卡培他滨的化学放射治疗后，在体外观察到的强大的放射增敏作用支持在直肠癌治疗中每日采用FTD / TPI和放射联合治疗方案。现在正在I / II期临床试验（NCT04177602）中对其进行测试。