Title : Nicaraven reduces cancer metastasis to irradiated lungs by decreasing CCL 8 and 1 macrophage recruitment 2 3

23 Radiotherapy for cancer patients damages normal tissues, thereby inducing an inflammatory 24 response and promoting cancer metastasis. We investigated whether nicaraven, a compound with 25 radioprotective and anti-inflammatory properties, could attenuate radiation-induced cancer 26 metastasis to the lungs of mice. Nicaraven and amifostine, another commercial radioprotective 27 agent, had limited effects on both the radiosensitivity of Lewis lung carcinoma cells in vitro and 28 radiation-induced tumor growth inhibition in vivo. Using experimental and spontaneous 29 metastasis models, we confirmed that thorax irradiation with 5 Gy X-rays dramatically increased 30 the number of tumors in the lungs. Interestingly, the number of tumors in the lungs was 31 significantly reduced by administering nicaraven but not by administering amifostine daily after 32 radiation exposure. Furthermore, nicaraven administration effectively inhibited CCL8 expression 33 and macrophage recruitment in the lungs 1 day after thorax irradiation. Our data suggest that 34 nicaraven attenuates radiation-induced lung metastasis, likely by regulating the inflammatory 35 response after radiation exposure. 36 37 38 Yan C. et al. Page 3