Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line.
BACKGROUND
With metastatic progression, gastric cancer is incurable. Using a DNA microarray, we performed differential gene expression analysis of established highly metastatic gastric cancer cell lines and compared the findings with those from a low-metastatic parental cell line. The results demonstrated that the endothelin A receptor (ET-A) gene was the only one from the highly metastatic cell lines that was generally up-regulated.


METHODS
To investigate the role that ET-A plays in gastric cancer metastasis, we studied the effect of an ET-A-selective antagonist, YM598, on cell proliferation, tumor growth, and liver metastasis of the highly liver metastatic cell line AZ-H5c, established from the low metastatic human gastric cancer cell line AZ-521.


RESULTS
An in vivo study using nude mice demonstrated that YM598 had a significant growth inhibition effect on AZ-H5c at doses of 0.5-10.0 mg/kg. The liver metastatic rate was also significantly reduced by YM598: control, 83.3%; 1 mg/kg dosage, 16.7%; 10 mg/kg, 20%; and pretreatment at 1 mg/kg, 16.7%. There was no evidence of gross toxicity resulting from the YM598 treatment.


CONCLUSIONS
The ET-A blockade by YM598 had a strong inhibitory effect against tumor growth and liver metastasis of the gastric cancer cell lines. These data suggest that YM598 has potential as a novel therapeutic agent for inhibiting liver metastasis of gastric cancer.
Fukui
Rika
R
First Department of Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Sapporo, Japan.
Nishimori
Hidefumi
H
Hata
Fumitake
F
Yasoshima
Takahiro
T
Ohno
Keisuke
K
Yanai
Yoshiyuki
Y
Kamiguchi
Kenjiro
K
Denno
Ryuichi
R
Sato
Noriyuki
N
Hirata
Koichi
K
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D065130:Endothelin A Receptor Antagonists; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D013449:Sulfonamides