Inhibition of growth of OV-1063 human epithelial ovarian cancers and c-jun and c-fos oncogene expression by bombesin antagonists

被引:34
作者
Chatzistamou, I
Schally, AV [1 ]
Sun, B
Armatis, P
Szepeshazi, K
机构
[1] Vet Affairs Med Ctr, Inst Endocrine Polypeptide & Canc, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Dept Med, Sect Expt Med, New Orleans, LA 70112 USA
关键词
cancer therapy; bombesin/GRP antagonists; LH-RH antagonist; ovarian tumours; c-jun; c-fos;
D O I
10.1054/bjoc.2000.1374
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mu g and 20 mu g 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 mu g 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 mu g 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 mu g per day. Exposure of OV-1063, UCl-107 and ES-2 ovarian carcinoma cells to RG-3940-II at 1 mu M 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. (C) 2000 Cancer Research Campaign.
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页码:906 / 913
页数:8
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