Inhibition of growth of MDA-MB-231 human breast cancer xenografts in nude mice by bombesin/gastrin-releasing peptide (GRP) antagonists RC-3940-II and RC-3095.
Bombesin or gastrin-releasing peptide (GRP) may act as autocrine growth factors and play a role in the initiation and progression of breast cancer. We investigated the effect of bombesin/GRP antagonists RC-3095 and RC-3940-II on the growth of the MDA-MB-231 oestrogen-independent human breast cancer cell line xenografted into female nude mice. Bombesin/GRP antagonists, RC-3095 and RC-3940-II, were administered subcutaneously twice daily at a dose of 10 micrograms for 5 weeks. The growth of MDA-MB-231 tumours was inhibited during the treatment, as shown by a reduction in tumour volume. RC-3940-II and RC-3095 significantly decreased the final tumour volume by 72.4% and 57.7%, respectively, and greatly reduced tumour weights. RC-3940-II also significantly increased tumour doubling time and appeared to be more effective than RC-3095 in inhibiting the growth of MDA-MB-231 breast cancers. Serum gastrin and insulin-like growth factor-I (IGF-I) levels in animals treated with RC-3095 or RC-3940-II showed no significant changes as compared with controls. There was a significant decrease in the number of binding sites for epidermal growth factor (EGF), as well as bombesin, in tumour cells after chronic treatment with RC-3095 or RC-3940-II, which might be related to inhibition of tumour growth. Reverse transcription polymerase chain reaction, followed by Southern blot analysis, also showed a reduction in the expression of mRNA for EGF receptors in the group treated with RC-3940-II. Our findings suggest that bombesin/GRP antagonists such as RC-3095 or RC-3940-II could be considered for endocrine therapy for oestrogen-independent breast cancers, but further investigations are necessary.
Endocrine, Polypeptide and Cancer Institute, Veterans' Affairs Medical Center, New Orleans, Louisiana 70146, USA.
M
M
Miyazaki
N
N
Lamharzi
A V
AV
Schally
G
G
Halmos
K
K
Szepeshazi
K
K
Groot
R Z
RZ
Cai
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015139:Blotting, Southern; D001839:Bombesin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D018004:Receptors, Bombesin; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D011949:Receptors, Cholecystokinin; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D066246:ErbB Receptors; D001839:Bombesin