SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells

Neurotensin (NT) is an autocrine growth factor for some small cell lung can cer (SCLC) cells. in this communication, the effects of a non-peptide NT re ceptor antagonist, SR48692, were investigated using SCLC cells. H-3-SR48692 bound with high affinity (IC50 = 20 nM) to NCI-H209 cells. Also, NT and SR 48692 inhibited specific I-125-NT binding with high affinity (IC50 values o f 2 and 200 nM). In contrast, the NT, receptor agonist, levocabastine, had little effect on specific I-125-NT binding, second messenger production and proliferation using NCI-H209 cells. SR-48692 (5 muM) antagonized the abili ty of NT (10 nM) to cause elevated cytosolic Ca2+ in Fura-2 AM loaded NCI-H 309 cells. SR48692 antagonized the ability of NT to cause elevation of c-fo s mRNA in these cells. Using a MTT proliferation assay, SR48692 inhibited N CI-H209 and H345 proliferation in a concentration-dependent manner. Using a clonogenic assay, 1 muM SR48692, reduced NCI-H209 colony number. Also, SR4 86392 (0.4 mg/kg per day) inhibited NCI-H209 xenograft proliferation in nud e mice. These results suggest that SR48692 is: a NT1 receptor antagonist wh ich inhibits SCLC growth. (C) 2001 Published by Elsevier Science Inc.