bombesin(6-14)--hca(6)-leu(13)-psi(ch2n)-tac(14)- and Breast-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Bombesin; Breast Neoplasms; Female; Fibroblast Growth Factors; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; Peptide Fragments; RNA, Messenger; Somatomedins; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

Previous studies showed that antagonists of bombesin (BN)/gastrin-releasing peptide (GRP) inhibit the growth of various cancers by interfering with the growth-stimulatory effects of BN-like peptides and down-regulating epidermal growth factor receptors on tumors. Because the overexpression of the human epidermal growth factor receptor-2 (ErbB-2/HER-2/neu) oncogene plays a role in the progression of many breast cancers, we investigated whether BN/GRP antagonists can affect HER-2 in mammary tumors. Female nude mice bearing orthotopic xenografts of MDA-MB-435 human estrogen-independent breast cancers were treated daily with BN/GRP antagonists RC-3095 (20 microg) or RC-3940-II (10 microg) for 6 weeks. The expression of BN/GRP receptors on tumors was analyzed by reverse transcription-PCR and immunoblotting. We also evaluated whether the mRNA expression for the c-jun and c-fos oncogenes is affected by the therapy. Both BN/GRP antagonists significantly inhibited growth of MDA-MB-435 cancers; RC-3095 reduced tumor volume by 40% and RC-3940-II by 65%. The GRP receptors (subtype 1) were detected in MDA-MB-435 tumors, showing that they mediate the inhibitory effect of the antagonists. Tumor inhibition was associated with a substantial reduction in the expression of mRNA and protein levels of the ErbB/HER receptor family as well as with a decrease in the expression of c-jun and c-fos oncogenes. BN/GRP antagonists RC-3940-II and RC-3095 could be considered for endocrine therapy of estrogen-independent breast cancers that express members of the ErbB/HER receptor family and the c-jun and c-fos oncogenes.

Topics: Adult; Animals; Bombesin; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Epidermal Growth Factor; Estrogens; Female; Gastrins; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, jun; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Receptor, ErbB-2; RNA, Messenger; Tumor Cells, Cultured

The growth of breast carcinoma is promoted by autocrine growth factors such as the bombesin (BN)-like peptides and epidermal growth factor (EGF). The stimulatory action of BN-like peptides can be blocked by the use of BN/gastrin-releasing peptide (GRP) antagonists.. The authors investigated the effects of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of mRNA for EGF receptors and three BN receptor subtypes in MDA-MB-468 human breast carcinoma. Athymic nude mice with xenografts of MDA-MB-468 human breast carcinoma were injected subcutaneously for 6 weeks with RC-3940-II at doses of 20 or 40 microg/day. In another study, the effects of RC-3940-II and RC-3095 were compared.. RC-3940-II caused a significant and dose-dependent growth inhibition of MDA-MB-468 tumors in nude mice; therapy with either dose of RC-3940-II significantly (P<0.01) reduced the mean final tumor volume and weight compared with controls. RC-3940-II induced a persistent regression of > 50% of all tumors. One of 3 tumors treated with 20 microg of RC-3940-II and 3 of 5 tumors treated with 40 microg were found to have regressed completely by the end of the study. When RC-3940-II and RC-3095 were compared at the dose of 20 microg/day, both powerfully suppressed growth of MDA-MB-468 tumors, with RC-3940-II causing a complete regression of 2 tumors and RC-3095 a complete regression of 1 tumor. Receptor analyses of untreated MDA-MB-468 tumors revealed an overexpression of EGF receptors and two classes of binding sites for BN/GRP. mRNAs for receptors of GRP, neuromedin B, and BN receptor subtype-3 were detected by reverse transcriptase-polymerase chain reaction.. A virtual arrest of growth or regression of MDA-MB-468 human breast carcinoma after therapy with RC-3940-II and RC-3095 indicates that these BN/GRP antagonists could provide a new treatment modality for breast tumors expressing BN and EGF receptors.

Topics: Animals; Antineoplastic Agents; Bombesin; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; ErbB Receptors; Female; Gastrin-Releasing Peptide; Gene Expression Regulation, Neoplastic; Humans; Injections, Subcutaneous; Mice; Mice, Nude; Neoplasm Transplantation; Neurokinin B; Peptide Fragments; Polymerase Chain Reaction; Receptors, Bombesin; Remission Induction; RNA, Messenger; Transplantation, Heterologous; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Agents; Blotting, Southern; Bombesin; Breast Neoplasms; Cell Division; ErbB Receptors; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Polymerase Chain Reaction; Radioimmunoassay; Receptors, Bombesin; Receptors, Cholecystokinin; RNA, Messenger; Transplantation, Heterologous