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

Cancer. 2000 Mar 15;88(6):1384-92. doi: 10.1002/(sici)1097-0142(20000315)88:6<1384::aid-cncr16>3.0.co;2-q.

Abstract

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 use of BN/gastrin-releasing peptide (GRP) antagonists.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Bombesin / administration & dosage
  • Bombesin / analogs & derivatives*
  • Bombesin / antagonists & inhibitors*
  • Bombesin / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Dose-Response Relationship, Drug
  • ErbB Receptors / drug effects
  • ErbB Receptors / genetics
  • Female
  • Gastrin-Releasing Peptide / antagonists & inhibitors*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Injections, Subcutaneous
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neurokinin B / analogs & derivatives
  • Neurokinin B / drug effects
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / therapeutic use*
  • Polymerase Chain Reaction
  • RNA, Messenger / drug effects
  • Receptors, Bombesin / classification
  • Receptors, Bombesin / drug effects
  • Receptors, Bombesin / genetics
  • Remission Induction
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Peptide Fragments
  • RNA, Messenger
  • Receptors, Bombesin
  • bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-
  • bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-
  • Gastrin-Releasing Peptide
  • Neurokinin B
  • neuromedin B
  • ErbB Receptors
  • Bombesin