Characterization 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.
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, beta-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.
Ito
Yuichi
Y
Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Nakanishi
Hayao
H
Kodera
Yasuhiro
Y
Hirai
Takashi
T
Nakao
Akimasa
A
Kato
Tomoyuki
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008875:Middle Aged; D010094:Oxonic Acid / Q000627:therapeutic use*; D005641:Tegafur / Q000008:administration & dosage / Q000627:therapeutic use*; D014498:Uracil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D002955:Leucovorin; D005472:Fluorouracil