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; Schally, AV; Sun, B; Armatis, P; Szepeshazi, K
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