Combination therapy of S-1 with selective cyclooxygenase-2 inhibitor for liver metastasis of colorectal carcinoma.
BACKGROUND
Hepatic resection, the only curative treatment for liver metastasis of colorectal cancer has become standard treatment, but most cases of liver metastases are inoperable, and of the patients treated with hepatectomy about 50% have a recurrence in the liver. The aim of this study was to establish preventive therapy for the liver metastasis of colorectal cancer.


METHODS
In this study, a combined treatment with S-1 and a selective COX-2 inhibitor for liver metastasis of colorectal cancer was developed. The effect of these agents on the proliferation and invasion of a highly metastatic human colon cancer cell line, LM-H3, was examined.


RESULTS
5-Fluorouracil (5-FU) had an inhibitory effect on the proliferation of LM-H3 cells, but no inhibitory effect on the invasion of LM-H3 cells in in vitro experiments. 5-Chloro-2,4-dihydroxypyridine (CDHP) had no antitumor activity itself, but the inhibitory effect of 5-FU on the proliferation was enhanced by adding CDHP. COX-2 inhibitors, etodolac and rofecoxib, did not have an inhibitory effect on the proliferation of LM-H3 cells at low concentrations, but had significant inhibitory effect on the invasion of LM-H3 cells in in vitro experiments. In a nude mouse liver metastasis model, combined treatment with S-1 and a COX-2 inhibitor more effectively restrained liver metastasis of LM-H3 cells than either alone. This outcome was most likely due to S-1 inhibiting proliferation of and the COX-2 inhibitor inhibiting invasion of LM-H3 cells.


CONCLUSIONS
Combined therapy with S-1 and a COX-2 inhibitor might hold promise for prophylaxis of liver metastasis of colorectal cancer.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Akiko
A
Tachimori
Nobuya
N
Yamada
Ryosuke
R
Amano
Masaichi
M
Ohira
Kosei
K
Hirakawa
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004338:Drug Combinations; D017308:Etodolac / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010094:Oxonic Acid / Q000008:administration & dosage*; D013450:Sulfones / Q000008:administration & dosage; D005641:Tegafur / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; C079198:S 1 (combination); D005641:Tegafur; D017308:Etodolac; D010094:Oxonic Acid