Inhibition of growth of OV-1063 human epithelial ovarian cancers and c- jun and c- fos oncogene expression by bombesin antagonists.
Receptors for bombesin are present on human ovarian cancers and bombesin-like peptides could function as growth factors in this carcinoma. Therefore, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists RC-3940-II and RC-3095 on the growth of human ovarian carcinoma cell line OV-1063, xenografted into nude mice. Treatment with RC-3940-II at doses of 10 microg and 20 microg per day s.c. decreased tumour volume by 60.9% (P< 0.05) and 73.5% (P< 0.05) respectively, after 25 days, compared to controls. RC-3095 at a dose of 20 microg per day reduced the volume of OV-1063 tumours by 47.7% (P = 0.15). In comparison, luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix at a dose of 100 microg per day caused a 64.2% inhibition (P< 0.05). RT-PCR analysis showed that OV-1063 tumours expressed mRNA for bombesin receptor subtypes BRS-1, BRS-2, and BRS-3. In OV-1063 cells cultured in vitro, GRP(14-27) induced the expression of mRNA for c- jun and c- fos oncogenes in a time-dependent manner. Antagonist RC-3940-II inhibited the stimulatory effect of GRP(14-27) on c- jun and c- fos in vitro. In vivo, the levels of c- jun and c- fos mRNA in OV-1063 tumours were decreased by 43% (P< 0.05) and 45% (P = 0. 05) respectively, after treatment with RC-3940-II at 20 microg per day. Exposure of OV-1063, UCI-107 and ES-2 ovarian carcinoma cells to RC-3940-II at 1 microM concentration for 24 h in vitro, extended the latency period for the development of palpable tumours in nude mice. Our results indicate that antagonists of bombesin/GRP inhibit the growth of OV-1063 ovarian cancers by mechanisms that probably involve the downregulation of c- jun and c- fos proto-oncogenes.
Chatzistamou
I
I
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Section of Experimental Medicine, New Orleans, LA, USA.
Schally
A V
AV
Sun
B
B
Armatis
P
P
Szepeshazi
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004848:Epithelium / Q000473:pathology; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects* / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects* / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018004:Receptors, Bombesin / Q000096:biosynthesis / Q000145:classification / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D006727:Hormone Antagonists; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018004:Receptors, Bombesin; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D007987:Gonadotropin-Releasing Hormone; D019886:Gastrin-Releasing Peptide; C062876:cetrorelix; D001839:Bombesin