Open AccessCharacterization of a novel lymph node metastasis model from human colonic cancer and its preclinical use for comparison of anti‐metastatic efficacy between oral S‐1 and UFT/ LV
Author(s) -
Ito Yuichi,
Nakanishi Hayao,
Kodera Yasuhiro,
Hirai Takashi,
Nakao Akimasa,
Kato Tomoyuki
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01607.x
Subject(s) - dihydropyrimidine dehydrogenase , medicine , colorectal cancer , thymidylate synthase , cancer research , micrometastasis , metastasis , cancer , in vivo , oncology , fluorouracil , biology , microbiology and biotechnology
Although lymph node metastasis (LNM) is the most critical prognostic factor in colorectal cancer patients, the anti‐LNM efficacy of chemotherapeutic agents is largely unknown because of the limitations of reproducible human colorectal cancer LNM models. Here, we developed a new LNM model from a recently established colorectal cancer cell line (COLM‐5) and compared the anti‐LNM efficacy of two oral formulations of 5‐fluorouracil (5‐FU) derivatives, S‐1 and UFT/leucovorin (LV). COLM‐5 cells is a poorly differentiated adenocarcinoma cell line with unique features such as left‐sided, β‐catenin cytoplasmic localization, and microsatellite stable phenotype. COLM‐5 cells expressed vascular endothelial growth factor (VEGF‐C) and exhibited peritumoral lymphangiogenesis. Consequently, they showed high LNM potential at an incidence of approximately 90% when subcutaneously injected into nude mice, allowing use for preclinical study. When chemotherapy with S‐1 or UFT/LV started from the micrometastasis stage, not the advanced macroscopic metastasis stage, anti‐LNM efficacy of S‐1 was significantly higher than that of UFT/LV at the dosage in which antitumor activity of the two drugs against primary subcutaneous tumor was comparable. COLM‐5 cells showed expression pattern of 5‐FU metabolizing enzymes such as high dihydropyrimidine dehydrogenase (DPD) and low thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT) both in vitro and in vivo . These results suggest that the preferential anti‐LNM activity of S‐1 compared with UFT/LV against high‐DPD COLM‐5 tumors is due to the higher DPD inhibitory activity of 5‐chloro‐2, 4‐dihydroxypyrimidine (CDHP) present in S‐1 than uracil in UFT. The COLM‐5 model would be an excellent tool for understanding the basic mechanism of LNM and for preclinical study on the anti‐LNM efficacy of the drugs. ( Cancer Sci 2010)