The attainment of chemoresistance during
tumor metastasis is often experienced. In this study, we evaluated the correlation between sensitivity to
5-fluorouracil (5-FU) and the
mRNA expression level of several 5-FU-related metabolic
enzymes [
thymidylate synthase,
dihydropyrimidine dehydrogenase (DPD), thymidylate
phosphorylase (TP), orotate phosphoribosyl
transferase, and
uridine phosphorylase] in primary
colorectal cancer and synchronous liver
metastases from ten patients to investigate how
colorectal cancer acquires
5-FU resistance during liver
metastases. A liver
metastasis model of xenotransplanted human
colon cancer cell line (HCT116) in nude mice and several cell lines from metastatic liver
tumors were also established and analyzed. Chemosensitivity and
mRNA expression levels were measured by using
collagen gel droplet-embedded culture
drug sensitivity tests and real-time quantitative reverse transcription-polymerase chain reaction. Metastatic liver
tumors were significantly more resistant to
5-FU than primary
colorectal cancer (T/C, 88.7% versus 69.7%, p<0.05). DPD and TP
mRNA levels were significantly higher in metastatic liver
tumors (DPD: 10.36+/-1.81 versus 3.95+/-0.99, p<0.01; and TP: 18.80+/-4.96 versus 7.28+/-1.23, p<0.05) and inversely correlated with
5-FU sensitivity (DPD: R=0.570, p<0.05; TP: R=0.600, p<0.05). In the mouse model, metastatic liver
tumors were significantly more resistant to
5-FU than HCT116 (T/C, 92.7%, 96.2% versus 68%, p<0.001). The DPD and TP
mRNA levels increased with repeated liver
metastases. DPD and TP may affect the acquisition of resistance to
5-FU during liver
metastasis of
colorectal cancer. This mouse model may be useful for analyzing the mechanisms of how
colorectal cancer acquires resistance to
5-FU during liver
metastases.