Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers.

Abstract

The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogen-independent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/GRP antagonists for 6 weeks. Daily administration of 20 microg of RC-3095 or 10 microg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33-46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.

• Authors: A M Bajo, A V Schally, K Groot, K Szepeshazi
• Journal: British journal of cancer (Br J Cancer) Vol. 90 Issue 1 Pg. 245-52 (Jan 12 2004) ISSN: 0007-0920 [Print] England
• PMID: 14710236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Peptide Fragments
• RNA, Messenger
• Somatomedins
• Vascular Endothelial Growth Factor A
• bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-
• bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-
• Fibroblast Growth Factors
• Bombesin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bombesin (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Breast Neoplasms (physiopathology)
• Female
• Fibroblast Growth Factors (biosynthesis, pharmacology)
• Humans
• Mice
• Mice, Nude
• Neovascularization, Pathologic
• Peptide Fragments (pharmacology)
• RNA, Messenger (biosynthesis)
• Somatomedins (biosynthesis, pharmacology)
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A (biosynthesis, pharmacology)