Komura Toshihiro, Miura Koh, Shirasaka Tetsuhiko, Ohnuma Shinobu, Shimada Miki, Kajiwara Taiki, Fujishima Fumiyoshi, Philchenkov Alex, Nakagawa Kei, Kudoh Katsuyoshi, Haneda Sho, Toshima Masahide, Kohyama Atsushi, Musha Hiroaki, Naitoh Takeshi, Shibata Chikashi, Unno Michiaki
Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Int J Clin Oncol. 2015 Feb;20(1):117-25. doi: 10.1007/s10147-014-0699-x. Epub 2014 May 8.
A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.
Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis.
Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP.
Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.
一项针对转移性结直肠癌（CRC）患者的S-1联合亚叶酸钙（S-1/LV）的临床试验显示出有前景的疗效；然而，胃肠道毒性非常严重，以至于尚未应用于临床。另一方面，有人提出隔日给予S-1以减轻不良事件，同时不降低其抗癌活性。我们目前的研究旨在证实S-1/LV隔日给药在体内异种移植肿瘤模型中的可行性。
将小鼠分为每日给药组（给药2周，随后停药2周）或隔日给药组（隔日给药4周），给予S-1/LV治疗，然后处死小鼠并切除异种移植肿瘤。我们比较了体重变化、粪便状况、黏膜损伤和骨髓抑制情况，并评估了不良反应、肿瘤体积、肿瘤生长抑制（TGI）以及Ki67、TUNEL、cIAP2和XIAP的表达，以评估抗肿瘤活性和肿瘤凋亡情况。
仅在每日给药组观察到严重体重减轻、腹泻、黏膜损伤和骨髓抑制；然而，在隔日给药组也观察到了一些骨髓抑制。隔日给药组的TGI优于每日给药组，这可能是由于cIAP2而非XIAP受到抑制导致的细胞凋亡所致。
我们的研究结果表明，S-1/LV隔日给药用于CRC治疗可在无严重不良反应的情况下实现高抗肿瘤活性，我们建议应对CRC患者进行该方案的临床试验。
