Bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung carcinoma.
BACKGROUND
Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/GRP on tumors such as small cell lung carcinoma (SCLC). Although several studies have addressed the intracellular events that follow the formation of the receptor-ligand complex, the mechanism of action of BN/GRP antagonists remains unclear.


METHODS
In this study the authors investigated the effect of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of epidermal growth factor receptors (EGF-R) in H-69 SCLC. Athymic nude mice xenografted with H-69 SCLC were treated subcutaneously for 5 weeks with RC-3095 and RC-3940-II at the dose of 10 microg/animal/day.


RESULTS
RC-3095 decreased tumor volume by approximately 50% (P < 0.05) and RC-3940-II by 70-60% (P < 0.01). Tumor burden also was significantly decreased in the groups treated with RC-3095 and RC-3940-II. Receptor analyses demonstrated high affinity binding sites for BN/GRP and EGF on the untreated H-69 SCLC tumors. After treatment with RC-3095 and RC-3940-II, the concentration of receptors for BN/GRP was decreased by 29.0% and 36.5%, respectively (both, P < 0.01) compared with controls, and EGF-R levels were reduced by 62.3% and 63.0%, respectively (both, P < 0.01). Reverse transcriptase-polymerase chain reaction and Southern blot analyses revealed that the levels of mRNA for EGF-R in tumors were lowered by 31% (P < 0.05) and 43% (P < 0.01), respectively, after treatment with RC-3095 and RC-3940-II.


CONCLUSIONS
This study indicates that the inhibition of growth of H-69 SCLC by BN/GRP antagonists RC-3095 and RC-3940-II is accompanied by a marked decrease in the levels and mRNA expression of EGF-R.
Koppán
M
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
Halmos
G
G
Arencibia
J M
JM
Lamharzi
N
N
Schally
A V
AV
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000032:analysis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C114782:TAA90K protein, human; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D066246:ErbB Receptors; D001839:Bombesin