Neurotensin and a non-peptide neurotensin receptor antagonist control human colon cancer cell growth in cell culture and in cells xenografted into nude mice

The intestine is a large endocrine organ, but: the dependence of colon canc er on hormones remains unknown. We show here that neurotensin, a paracrine/ endocrine peptide in the gut, and the neurotensin receptor antagonist SR 48 692 control colon cancer cell growth in vitro and in vivo by interacting wi th receptors that are ectopically expressed in colon cancers. In cell cultu re, neurotensin stimulates the growth of human colon cancer cell lines (SW4 80, SW620, HT29, HCT116 and C1.19A) expressing the neurotensin receptor NTR I but: does not change the growth of Caco2 cells, which do not: express NTR I. In SW480 cells, neurotensin is active in the 10(-10) to 10(-6) M concent ration range (ED50 = 0.47 nM) while the neurotensin fragment(l-l I) is inac tive, Neurotensin also enhances the cellular cloning efficiency of SW480 ce lls in soft agar by inducing a 50% increase of colony formation, This effec t is blocked by SR 48692, which alone does not alter colony formation. Subc utaneous delivery of neurotensin (0.54 mu mol/kg every 24 hr) by osmotic pu mps to nude mice that have been xenografted with SW480 cells results in a s ignificant increase of tumor volume, Le, up to 255% of control at: day 20 o f treatment. SR 48632 administered alone (1.7 mu mol/kg every 24 hr) by dai ly i.p. injections reduces the development of tumors formed by xenografting SW480 cells in nude mice. A significant mean reduction of tumor volume of 38% is observed during the 22-day period of treatment. SR 48692 alone is al so active at reducing tumor volume after xenografting HCT116 cells in nude mice. Our results support the notion that colon cancer growth may be depend ent on blood borne neurotensin and suggest that non-peptide neurotensin ant agonists, such as SR 48692, may be useful for the development: of novel the rapeutic strategies of colon cancer, (C) 1999 Wiley-Liss, Inc.