Anti-metastatic effect of capecitabine on human colon cancer xenografts in nude mouse rectum.
Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) by 3 sequential steps of enzyme reactions. We investigated the possibility of using capecitabine to prevent metastasis with a metastasis model of gastrointestinal cancer developed by the intrarectal injection of green fluorescent protein (GFP)-expressing colon cancer HT-29 cells (HT-29-GFP) into nude mice. Lung and lymph node metastasis in the HT-29-GFP rectal xenograft was assessed through both observation of GFP fluorescence and quantification of metastasis by amplification of a cancer-related human DNA by TaqMan PCR. Furthermore, for each organ, we examined mRNA levels of cancer-specific thymidine phosphorylase (dThdPase), which is an essential enzyme for capecitabine activation, by the quantitative RT-PCR method. Capecitabine inhibited the HT-29-GFP xenograft growth by 60.8% and 43.8% in the subcutaneous and rectal xenograft models, respectively. Furthermore, it inhibited both lung and lymph node metastasis by 99.9%. dThdPase expression in the tumor cells of both the rectal xenograft and metastatic lung tumor cells was upregulated by 10.0- and 24.3-fold that in the HT-29-GFP cells in vitro, respectively. These results indicated that capecitabine might effectively inhibit or suppress metastasis via upregulation of dThdPase expression. Capecitabine administration might be highly expected to reduce metastasis and improve survival of patients with gastrointestinal cancers.
Ninomiya
Itasu
I
Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa Japan. nino@surg2m.kanazawa-u.ac.jp
Terada
Itsuro
I
Yoshizumi
Tetsuya
T
Takino
Takahisa
T
Nagai
Noboru
N
Morita
Akihiko
A
Fushida
Sachio
S
Nishimura
Genichi
G
Fujimura
Takashi
T
Ohta
Tetsuo
T
Miwa
Koichi
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000069287:Capecitabine; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005472:Fluorouracil / Q000031:analogs & derivatives; D005770:Gastrointestinal Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D000964:Antimetabolites, Antineoplastic; D008164:Luminescent Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003841:Deoxycytidine; D049452:Green Fluorescent Proteins; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil