Manabe Yoshihiko, Takahashi Yutaka, Sugie Chikao, Wang Zhen, Katsuki Shohei, Kondo Takuhito, Murai Taro, Nakashima Masahiro, Takaoka Taiki, Ogawa Kazuhiko, Shibamoto Yuta
Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Osaka, Japan.
Transl Cancer Res. 2023 Feb 28;12(2):351-358. doi: 10.21037/tcr-22-1857. Epub 2023 Jan 29.
Prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four receptors (EP1-4). We investigated the radiosensitizing effects of a newly developed antagonist of PGE2-EP4 (AAT-008) in mouse colon cancer cells and explored the mechanism using flow cytometry (FCM).
CT26WT cells grown in Balb/c mice were used. AAT-008 at doses of 0, 3, 10, and 30 mg/kg/day was orally administered once or twice daily for up to 19 days. On day 3, the tumors were irradiated at 9 Gy in the radiotherapy (RT) group. Tumor sizes were measured every other day. For the first FCM series, AAT-008 (10 mg/kg/day) was administered from day 0 to 18 and RT (9 Gy) was given on day 3. The population of effector T cells (Teff), defined as CD45CD8CD69, in the tumors was investigated on day 19. For the second FCM series, AAT-008 (30 mg/kg/day) was administered from day 0 to 12. The populations of Teff and regulatory T cells (Treg), and the ratio of Teff/Treg were investigated on day 13.
The growth delay effect of AAT-008 administered alone (3-30 mg/kg/day) appeared minimal. In the first growth delay experiment where AAT-008 was administered once daily, the combined effect of AAT-008 (30 mg/kg/day) and RT appeared additive. In the second growth delay experiment where AAT-008 was administered twice daily, the combined effect appeared additive at 3 and 10 mg/kg/day and supra-additive at 30 mg/kg/day. In the first FCM series, the mean Teff proportions in the tumors were 43% and 31% in the 10 mg + RT and 0 mg + RT groups, respectively. Notably, 67% Teff was observed in responsive mice in the 10 mg + RT group. In the second FCM series, the mean Treg proportion and Teff/Treg ratio in the 0 mg + RT and 30 mg + RT groups were 4.0% and 1.5%, respectively (P=0.04) and 10 and 22, respectively (P=0.04).
AAT-008 potentially enhances the radiosensitivity of colon cancer cells, apparently by stimulating the immune system against the cancer cells.
前列腺素E2（PGE2）通过作用于四种受体（EP1 - 4）家族促进肿瘤生长和转移。我们研究了新开发的PGE2 - EP4拮抗剂（AAT - 008）对小鼠结肠癌细胞的放射增敏作用，并使用流式细胞术（FCM）探索其机制。
使用在Balb/c小鼠体内生长的CT26WT细胞。AAT - 008剂量为0、3、10和30 mg/kg/天，每天口服一次或两次，持续19天。在第3天，放疗（RT）组肿瘤接受9 Gy照射。每隔一天测量肿瘤大小。对于第一个FCM系列实验，从第0天至第18天给予AAT - 008（10 mg/kg/天），并在第3天给予RT（9 Gy）。在第19天研究肿瘤中效应T细胞（Teff，定义为CD45CD8CD69）的比例。对于第二个FCM系列实验，从第0天至第12天给予AAT - 008（30 mg/kg/天）。在第13天研究Teff和调节性T细胞（Treg）的比例以及Teff/Treg比值。
单独给予AAT - 008（3 - 30 mg/kg/天）的生长延迟效应似乎最小。在第一个每天给药一次的生长延迟实验中，AAT - 008（30 mg/kg/天）与RT的联合效应呈相加性。在第二个每天给药两次的生长延迟实验中，3和10 mg/kg/天的联合效应呈相加性，30 mg/kg/天呈超相加性。在第一个FCM系列实验中，10 mg + RT组和0 mg + RT组肿瘤中Teff的平均比例分别为43%和31%。值得注意的是，在10 mg + RT组的反应性小鼠中观察到67%的Teff。在第二个FCM系列实验中，0 mg + RT组和30 mg + RT组的平均Treg比例和Teff/Treg比值分别为4.0%和1.5%（P = 0.04）以及10和22（P = 0.04）。
AAT - 008可能增强结肠癌细胞的放射敏感性，显然是通过刺激针对癌细胞的免疫系统实现的。
