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

• Published in: International journal of clinical oncology Vol. 20; no. 1; pp. 117 - 125
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.02.2015; Springer Nature B.V
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Cancer Research; Cell Line, Tumor; Chemotherapy; Colorectal cancer; Colorectal Neoplasms - drug therapy; Drug Administration Schedule; Drug Combinations; Drug dosages; Drug-Related Side Effects and Adverse Reactions - prevention & control; Heterografts; HT29 Cells; Humans; Leucovorin - administration & dosage; Leucovorin - adverse effects; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Oncology; Original Article; Oxonic Acid - administration & dosage; Oxonic Acid - adverse effects; Rodents; Side effects; Surgical Oncology; Tegafur - administration & dosage; Tegafur - adverse effects; In vivo mouse model; Leucovorin; Alternate-day administration; S-1; Colorectal cancer
• ISSN: 1341-9625; 1437-7772
• DOI: 10.1007/s10147-014-0699-x

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 (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. 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.