Neoadjuvant chemoradiation (nCRT) followed by surgery represents the standard of care in patients with locally advanced rectal cancer. Increasing radiotherapy (RT) doses and chemotherapy cycles with 5FU have been associated with increased rates of complete response, however these strategies imply significant toxicity. In the last years, epidemiologic findings have demonstrated that metformin is associated with significantly higher rates of pathological complete response to nCRT. Also, pre-clinical studies using cell lines provide evidence for the radiosensitive effect of metformin. However, no studies have been performed using rectal cancer patient samples to test this radiosensitive effect of metformin and compared it to the standard 5FU. Here, we designed an experimental study to compare both radiosensitizers in the zebrafish xenograft model (zAvatar), using rectal cancer surgical specimens and diagnostic biopsies. Patient zAvatars confirmed that metformin has indeed a powerful in vivo radiosensitizer effect, similar to 5FU. Our work confirms that metformin constitutes a promising less toxic alternative to the standard 5FU, which could be game changing in elderly/frail patients to optimize tumor regression.

新辅助放化疗 (nCRT) 后进行手术是局部晚期直肠癌患者的护理标准。增加放疗 (RT) 剂量和 5FU 化疗周期与增加完全缓解率有关，但这些策略意味着显着的毒性。过去几年，流行病学研究结果表明，二甲双胍与 nCRT 的病理完全反应率显着升高有关。此外，使用细胞系的临床前研究为二甲双胍的放射敏感性效应提供了证据。然而，尚未使用直肠癌患者样本进行研究来测试二甲双胍的这种放射敏感性效应并将其与标准 5FU 进行比较。这里，我们设计了一项实验研究，使用直肠癌手术标本和诊断活检比较斑马鱼异种移植模型 (zAvatar) 中的两种放射增敏剂。患者 zAvatars 证实二甲双胍确实具有强效体内放射增敏剂作用，类似于 5FU。我们的工作证实，二甲双胍是标准 5FU 的一种有希望的毒性较小的替代品，这可能会改变老年/体弱患者的游戏规则，以优化肿瘤消退。