The ability of reduced peptide bond analogues of gastrin releasing peptide (GRP) to antagonize small cell lung cancer (SCLC) GRP receptors was investigated. BW462U89, BW1023U90, BW2123U89 and BW2258U89 inhibited binding of (125I-Tyr4) BN to NCI-H345 cells with IC50 values of 5, 6, 140 and 10 nM respectively. The GRP analogues had no effect on basal cytosolic Ca2+ but inhibited the increase caused by 10 nM BN. BW462U89 reversibly blocked the increase in cytosolic Ca2+ caused by BN. The GRP analogues (1 microM) inhibited NCI-H345 colony formation in the absence or presence of 10 nM BN. Also, BW2258U89 (0.4 mg/kg, s.c. daily) inhibited xenograft growth in nude mice. These data indicate that BW2258U89 inhibits SCLC growth in vitro and in vivo.