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Bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II inhibit tumor growth and decrease the levels
M Koppán1, G Halmos, J M Arencibia
1Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
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.
Insights
Bombesin/gastrin-releasing peptide (BN/GRP) antagonists RC-3095 and RC-3940-II significantly reduced small cell lung carcinoma (SCLC) tumor growth. These BN/GRP antagonists also decreased epidermal growth factor receptor (EGF-R) levels and mRNA expression in SCLC tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bombesin/gastrin-releasing peptide (BN/GRP) antagonists are developed to inhibit tumor growth in cancers like small cell lung carcinoma (SCLC) by blocking autocrine stimulatory effects.
- The precise mechanism of action for BN/GRP antagonists, particularly concerning intracellular events and receptor modulation, remains incompletely understood.
Purpose of the Study:
- To investigate the effects of synthetic BN/GRP antagonists, RC-3095 and RC-3940-II, on tumor growth in H-69 SCLC models.
- To examine the impact of these antagonists on the expression of epidermal growth factor receptors (EGF-R) within SCLC tumors.
Main Methods:
- Athymic nude mice xenografted with H-69 SCLC were treated subcutaneously for 5 weeks with BN/GRP antagonists RC-3095 and RC-3940-II.
- Tumor volume, burden, and receptor expression levels (BN/GRP and EGF-R) were quantified.
- Reverse transcriptase-polymerase chain reaction and Southern blot analyses were used to assess EGF-R mRNA levels.
Main Results:
- Both RC-3095 and RC-3940-II significantly reduced H-69 SCLC tumor volume and burden.
- Treatment with BN/GRP antagonists led to a significant decrease in the concentration of BN/GRP receptors and EGF-R.
- A marked reduction in EGF-R mRNA levels was observed in tumors treated with RC-3095 and RC-3940-II.
Conclusions:
- BN/GRP antagonists RC-3095 and RC-3940-II effectively inhibit the growth of H-69 SCLC.
- The anti-tumor effect of these BN/GRP antagonists is associated with a significant downregulation of EGF-R expression at both protein and mRNA levels.