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- Title
Inhibition of neurotensin-induced pancreatic carcinoma growth by a nonpeptide neurotensin receptor antagonist, SR48692.
- Authors
Iwase, Kazuhiro; Evers, B. Mark; Hellmich, Mark R.; Kim, Hong Jin; Higashide, Shunichi; Gully, Danielle; Thompson, James C.; Townsend, Courtney M.; Iwase, K; Evers, B M; Hellmich, M R; Kim, H J; Higashide, S; Gully, D; Thompson, J C; Townsend, C M Jr
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>(125)I-NT binding and Northern blot analyses were performed for evaluation of the NT receptor in MIA PaCa-2 cells. Intracellular calcium ([Ca2+]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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
Cancer (0008543X), 1997, Vol 79, Issue 9, p1787
- ISSN
0008-543X
- Publication type
journal article
- DOI
10.1002/(SICI)1097-0142(19970501)79:9<1787::AID-CNCR22>3.0.CO;2-T