The endothelin system in Morris hepatoma-7777: an endothelin receptor antagonist inhibits growth in vitro and in vivo.
1. Plasma concentrations of endothelin are increased in patients with hepatocellular cancer as well as in patients with liver metastasis. However, the impact of these findings remains uncertain. 2. We thus analyzed the endothelin system in a rat hepatoma model (Morris hepatoma 7777) in vitro and in vivo. 3. Our study revealed that tissue concentrations of endothelin-1 (ET-1) and big-ET-1, the precursor of ET-1, were significantly elevated in Morris hepatoma 7777 as compared to normal liver. The ETA receptor density was significantly elevated, whereas the density of the ETB receptor was decreased in Morris hepatoma 7777. 4. We could also demonstrate that hepatoma cells secrete ET-1. 5. Exogenously added ET-1 enhances hepatoma cell growth in a dose-dependent manner. Endothelin receptor antagonists (ETA and combined ETA/ETB receptor antagonists) inhibit tumor cell growth in vitro. Since the combined ETA/ETB receptor antagonist was more effective in vitro, we used this compound also for in vivo studies and could demonstrate that a combined ETA/ETB receptor antagonist is able to reduce hepatoma growth in vivo. 6. In conclusion, the endothelin system is activated in Morris hepatoma 7777 and contributes to hepatoma growth. Since endothelin receptor antagonists are well-tolerated upcoming clinically used drugs without major side effects, our data might provide a new pharmacological approach to reduce hepatoma growth in vivo.
Pfab
Thiemo
T
Center for Cardiovascular Research (CCR)/Department of Nephrology, Medical School Charité, Humboldt University of Berlin, Germany.
Stoltenburg-Didinger
Gisela
G
Trautner
Christoph
C
Godes
Michael
M
Bauer
Christian
C
Hocher
Berthold
B
D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011915:Rats, Inbred BUF; D017466:Receptors, Endothelin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006131:Growth Inhibitors; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D017466:Receptors, Endothelin