caa a22 4500 605490368 CHVBK 20210128100504.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10147-014-0699-x doi (NATIONALLICENCE)springer-10.1007/s10147-014-0699-x Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: a shorter drug-free interval leads to more efficient antitumor effects [Elektronische Daten] [Toshihiro Komura, Koh Miura, Tetsuhiko Shirasaka, Shinobu Ohnuma, Miki Shimada, Taiki Kajiwara, Fumiyoshi Fujishima, Alex Philchenkov, Kei Nakagawa, Katsuyoshi Kudoh, Sho Haneda, Masahide Toshima, Atsushi Kohyama, Hiroaki Musha, Takeshi Naitoh, Chikashi Shibata, Michiaki Unno] Background: 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. Methods: Mice were treated with S-1/LV in a daily group (2weeks of administration followed by 2weeks of withdrawal) or an alternate-day group (administration on alternate days for 4weeks), 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. Results: 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. Conclusion: 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. Japan Society of Clinical Oncology, 2014 S-1 nationallicence Leucovorin nationallicence Alternate-day administration nationallicence Colorectal cancer nationallicence In vivo mouse model nationallicence S-1/LV : S-1 and leucovorin nationallicence CRC : Colorectal cancer nationallicence TGI : Tumor growth inhibition nationallicence 5-FU : 5-Fluorouracil nationallicence GI : Gastrointestinal nationallicence FT : Tegafur nationallicence CDHP : 5-Chloro-2,4-dihydroxypyridine nationallicence Oxo : Potassium oxonate nationallicence LV : Leucovorin nationallicence HPMC : Hydroxypropyl methyl cellulose nationallicence BWC : Body weight change nationallicence TUNEL : Terminal deoxynucleotidyl transferase-mediated nick end labeling nationallicence SD : Standard deviation of mean nationallicence FdUMP : 5-Fluorodeoxyuridine-5′-monophosphate nationallicence 5,10-CH2-THF : 5,10-Methylene-tetrahydrofolate nationallicence TS : Thymidylate synthase nationallicence IAP : Inhibitor of apoptosis protein nationallicence NLRP3 : NOD-like receptor family, pyrin domain containing 3 nationallicence Komura Toshihiro Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Miura Koh Department of Surgery, Miyagi Cancer Center, 47-1 Nodayama, Shiote, Medeshima, 981-1293, Natori, Miyagi, Japan aut Shirasaka Tetsuhiko Kitasato Institute for Life Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, 108-8641, Tokyo, Japan aut Ohnuma Shinobu Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Shimada Miki Pharmaceutical Science, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Kajiwara Taiki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Fujishima Fumiyoshi Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Philchenkov Alex R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, 45 Vasylkivska Street, 03022, Kyiv, Ukraine aut Nakagawa Kei Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Kudoh Katsuyoshi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Haneda Sho Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Toshima Masahide Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Kohyama Atsushi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Musha Hiroaki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Naitoh Takeshi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Shibata Chikashi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut Unno Michiaki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut International Journal of Clinical Oncology Springer Japan 20/1(2015-02-01), 117-125 1341-9625 20:1<117 2015 20 10147 https://doi.org/10.1007/s10147-014-0699-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10147-014-0699-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Komura Toshihiro Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Miura Koh Department of Surgery, Miyagi Cancer Center, 47-1 Nodayama, Shiote, Medeshima, 981-1293, Natori, Miyagi, Japan aut NATIONALLICENCE 700 1- Shirasaka Tetsuhiko Kitasato Institute for Life Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, 108-8641, Tokyo, Japan aut NATIONALLICENCE 700 1- Ohnuma Shinobu Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Shimada Miki Pharmaceutical Science, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Kajiwara Taiki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Fujishima Fumiyoshi Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Philchenkov Alex R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, 45 Vasylkivska Street, 03022, Kyiv, Ukraine aut NATIONALLICENCE 700 1- Nakagawa Kei Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Kudoh Katsuyoshi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Haneda Sho Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Toshima Masahide Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Kohyama Atsushi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Musha Hiroaki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Naitoh Takeshi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Shibata Chikashi Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 700 1- Unno Michiaki Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan aut NATIONALLICENCE 773 0- International Journal of Clinical Oncology Springer Japan 20/1(2015-02-01), 117-125 1341-9625 20:1<117 2015 20 10147