Yoshiaki Fujimoto1, Ryota Nakanishi1, Mamoru Nukatsuka2, Kazuaki Matsuoka2, Koji Ando1, Takeshi Wakasa2,3, Hiroyuki Kitao4, Eiji Oki1, Yoshihiko Maehara1,5, Masaki Mori1. 1. Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Translational Research Laboratory, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan. 3. Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. 4. Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. hkitao@phar.kyushu-u.ac.jp. 5. Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.
Abstract
PURPOSE: Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model. METHODS: Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed. RESULTS: FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days. CONCLUSION: These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.
PURPOSE:Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model. METHODS:Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed. RESULTS:FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days. CONCLUSION: These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.
Authors: Robert J Mayer; Eric Van Cutsem; Alfredo Falcone; Takayuki Yoshino; Rocio Garcia-Carbonero; Nobuyuki Mizunuma; Kentaro Yamazaki; Yasuhiro Shimada; Josep Tabernero; Yoshito Komatsu; Alberto Sobrero; Eveline Boucher; Marc Peeters; Ben Tran; Heinz-Josef Lenz; Alberto Zaniboni; Howard Hochster; James M Cleary; Hans Prenen; Fabio Benedetti; Hirokazu Mizuguchi; Lukas Makris; Masanobu Ito; Atsushi Ohtsu Journal: N Engl J Med Date: 2015-05-14 Impact factor: 91.245