Inhibition of growth of MDA-MB-468 estrogen-independent human breast carcinoma by bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II

BACKGROUND, 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 us e of BN/gastrin-releasing peptide (GRP) antagonists. METHODS. The authors investigated the effects of synthetic BN/GRP antagonis ts RC-3095 and RC-3940-II on tumor growth and the expression of mRNA for EG F receptors and three BN receptor subtypes in MDA-MB-468 human breast carci noma. Athymic nude mice with xenografts of MDA-MB-468 human breast carcinom a were injected subcutaneously for 6 weeks with RC-3940-II at doses of 20 o r 40 mu g/day. In another study, the effects of RC-3940-II and RC-3095 were compared. RESULTS. RC-3940-II caused a significant and dose-dependent growth inhibiti on of MDA-MB-468 tumors in nude mice; therapy with either dose of RC-3940-I I significantly (P < 0.01) reduced the mean final tumor volume and weight c ompared with controls. RC-3940-II induced a persistent regression of > 50% of all tumors. One of 3 tumors treated with 20 mu g of RC-3940-II and 3 of 5 tumors treated with 40 mu g were found to have regressed completely by th e end of the study. When RC-3940-II and RC-3095 were compared at the dose o f 20 mu g/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 complet e regression of 1 tumor. Receptor analyses of untreated MDA-MB-468 tumors r evealed an overexpression of EGF receptors and two classes of binding sites for BN/GRP. mRNAs for receptors of GRP, neuromedin B, and BN receptor subt ype-3 were detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS. A virtual arrest of growth or regression of MDA-MB-468 human b reast carcinoma after therapy with RC-3940-II and RC-3095 indicates that th ese BN/GRP antagonists could provide a new treatment modality for breast tu mors expressing BN and EGF receptors. Cancer 2000;88:1384-92. (C) 2000 Amer ican Cancer Society.