Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

• Published in: British journal of cancer 2004-01, Vol.90 (1), p.245-252
• Main Authors: Bajo, A M, Schally, A V, Groot, K, Szepeshazi, K
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood vessels; Bombesin - analogs & derivatives; Bombesin - antagonists & inhibitors; Bombesin - pharmacology; Breast cancer; Breast Neoplasms - physiopathology; Cancer Research; Cancer therapies; Drug Resistance; Enzymes; Epidemiology; Experimental Therapeutics; Female; Fibroblast Growth Factors - biosynthesis; Fibroblast Growth Factors - pharmacology; Fibroblasts; Gynecology. Andrology. Obstetrics; Humans; Insulin-like growth factors; Kinases; Ligands; Mammary gland diseases; Medical prognosis; Medical research; Medical sciences; Mice; Mice, Nude; Molecular Medicine; Neovascularization, Pathologic; Oncology; Peptide Fragments - pharmacology; RNA, Messenger - biosynthesis; Somatomedins - biosynthesis; Somatomedins - pharmacology; Transplantation, Heterologous; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601404

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  μ g of RC-3095 or 10  μ g 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.