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


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.
Iwase
K
K
First Department of Surgery, Osaka University Medical School, Japan.
Evers
B M
BM
Hellmich
M R
MR
Kim
H J
HJ
Higashide
S
S
Gully
D
D
Thompson
J C
JC
Townsend
C M
CM
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D006868:Hydrolysis; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009496:Neurotensin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D019269:Phosphatidylinositol 4,5-Diphosphate; D011720:Pyrazoles; D011804:Quinolines; D012333:RNA, Messenger; D018028:Receptors, Neurotensin; C079087:SR 48692; D009496:Neurotensin; D002118:Calcium