Inhibition of neurotensin-induced pancreatic carcinoma growth by a nonpeptide neurotensin receptor antagonist, SR48692

Kazuhiro Iwase, B. Mark Evers, Mark Hellmich, Hong Jin Kim, Shunichi Higashide, Danielle Gully, James C. Thompson, Courtney Townsend

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

BACKGROUND. Recently, a nonpeptide neurotensin (NT) receptor antagonist, SR48692, was developed that selectively antagonizes the high affinity, biologically active NT binding site. The effect of SR48692 on NT-mediated growth of a human pancreatic carcinoma, MIA PaCa-2, was determined both in vitro and in vivo. METHODS. 125I-NT binding and Northern blot analyses were performed for evaluation of the NT receptor in MIA PaCa-2 cells. Intracellular calcium ([Ca2+l(i)) mobilization and inositol phosphate (IP3) levels were measured. Cell growth studies were performed by counting cell numbers. Athymic nude mice were inoculated with MIA PaCa-2 cells and randomized into four groups to receive either vehicle (NT or SR48692) or NT + SR48692. RESULTS. MIA PaCa-2 cells possess both a high affinity, SR48692- sensitive and a levocabastine-insensitive NT binding site; Northern blot analysis demonstrated expression of the NT receptor. SR48692 inhibited [Ca2+](i) mobilization, IP3 turnover, and MIA PaCa-2 cell growth induced by NT in a dose-dependent fashion. In in vivo experiments, NT significantly increased the size, weight, and DNA and protein content of xenografted MIA PaCa-2 tumors; SR48692 inhibited the effect of NT. CONCLUSIONS. The novel NT receptor antagonist SR48692 will be a valuable agent to delineate further the cellular mechanisms responsible for peptide-mediated growth of normal and neoplastic gut tissues.

Original languageEnglish (US)
Pages (from-to)1787-1793
Number of pages7
JournalCancer
Volume79
Issue number9
DOIs
StatePublished - May 1 1997

    Fingerprint

Keywords

  • neurotensin
  • neurotensin receptor antagonist
  • pancreatic carcinoma
  • SR48692

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this