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Inhibition of neurotensin‐induced pancreatic carcinoma growth by a nonpeptide neurotensin receptor antagonist, SR48692
Author(s) -
Iwase Kazuhiro,
Evers B. Mark,
Hellmich Mark R.,
Kim Hong Jin,
Higashide Shunichi,
Gully Danielle,
Thompson James C.,
Townsend Courtney M.
Publication year - 1997
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19970501)79:9<1787::aid-cncr22>3.0.co;2-t
Subject(s) - biology , neurotensin , receptor , in vivo , receptor antagonist , antagonist , cell growth , cell culture , microbiology and biotechnology , medicine , endocrinology , biochemistry , neuropeptide , genetics
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 125 I‐NT binding and Northern blot analyses were performed for evaluation of the NT receptor in MIA PaCa‐2 cells. Intracellular calcium ([Ca 2+ ] i ) mobilization and inositol phosphate (IP 3 ) 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 [Ca 2+ ] i mobilization, IP 3 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. Cancer 1997; 79:1787‐93. © 1997 American Cancer Society.