Antagonists of growth hormone-releasing hormone and somatostatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice.
The effects of antagonists of GHRH and the somatostatin analog RC-160 on the growth of OV-1063 human epithelial ovarian cancer cells xenografted into nude mice were investigated. Treatment with 20 microg/day of the GHRH antagonist JV-1-36 or MZ-5-156 and 60 microg/day of the somatostatin analog RC-160 for 25 days decreased tumor volume by 70.9% (P < 0.01), 58.3% (P < 0.05), and 60.6% (P < 0.01), respectively, vs. the control value. The levels of GH in serum were decreased in all of the treated groups, but only RC-160 significantly reduced serum insulin-like growth factor I (IGF-I). The levels of messenger ribonucleic acid (mRNA) for IGF-I and -II and for their receptors in OV-1063 tumors were investigated by multiplex RT-PCR. No expression of mRNA for IGF-I was detected, but treatment with JV-1-136 caused a 51.8% decrease (P < 0.05) in the level of mRNA for IGF-II in tumors. Exposure of OV-1063 cells cultured in vitro to GHRH, IGF-I, or IGF-II significantly (P < 0.05) stimulated cell growth, but 10(-5) mol/L JV-1-36 nearly completely inhibited (P < 0.001) OV-1063 cell proliferation. OV-1063 tumors expressed mRNA for GHRH receptors and showed the presence of binding sites for GHRH. Our results indicate that antagonistic analogs of GHRH and the somatostatin analog RC-160 inhibit the growth of epithelial ovarian cancers. The effects of RC-160 seem to be exerted more on the pituitary GH-hepatic IGF-I axis, whereas GHRH antagonists appear to reduce IGF-II production and interfere with the autocrine regulatory pathway. The antitumorigenic action of GHRH antagonists appears to be mediated by GHRH receptors found in OV-1063 tumors.
Chatzistamou
I
I
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Schally
A V
AV
Varga
J L
JL
Groot
K
K
Armatis
P
P
Busto
R
R
Halmos
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C403071:JV 1-36; C106656:MZ 5-156; D012333:RNA, Messenger; C051458:vapreotide; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone