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Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsRika Fukui, Hidefumi Nishimori, Fumitake Hata, Takahiro Yasoshima, Keisuke Ohno, Yoshiyuki Yanai, Kenjiro Kamiguchi, Ryuichi Denno, Noriyuki Sato, Koichi Hirata
JournalGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 10 Issue 2 Pg. 123-8 ( 2007) ISSN: 1436-3291 [Print] Japan
PMID17577623 (Publication Type: Journal Article)
Chemical References
  • Endothelin A Receptor Antagonists
  • N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide
  • Pyrimidines
  • RNA, Messenger
  • Receptor, Endothelin A
  • Sulfonamides
Topics
  • Animals
  • Cell Proliferation (drug effects)
  • Endothelin A Receptor Antagonists
  • Female
  • Flow Cytometry
  • Humans
  • Liver Neoplasms (prevention & control, secondary)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oligonucleotide Array Sequence Analysis
  • Pyrimidines (therapeutic use)
  • RNA, Messenger (genetics, metabolism)
  • Receptor, Endothelin A (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms (drug therapy, pathology)
  • Sulfonamides (therapeutic use)
  • Tumor Cells, Cultured

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