BW1023U90 - A NEW GRP RECEPTOR ANTAGONIST FOR SMALL-CELL LUNG-CANCER CELLS

Gastrin-releasing peptide (GRP) receptor antagonists were synthesized and their ability to interact with small-cell lung cancer (SCLC) cells determined. [I-125]BW1023U90, bound with high affinity (K-d = 2 nM) t o a single class of sites (Bmax = 55 fmol/mg protein) using SCLC cell line NCI-H345. [I-125]BW1023U90 binding was time dependent and reversi ble even at 37 degrees C as the ligand was minimally internalized. Spe cific [I-125]BW1023U90 binding was inhibited with high affinity by GRP as well as bombesin (BB) but not neuromedin B (NMB). BW1023U90 inhibi ted the ability of BB to elevate cytosolic Ca2+ and increase the growt h of SCLC cells. A BW1023U90 analogue, BW2258U89 10 mu g/day, SC) slow ed SCLC xenograft formation in nude mice and [I-125]BW1023U90 localize d to SCLC tumors 1 h after injection into nude mice. BW2258U89 (4% by weight) was placed in microspheres and slowly released over a 3-week p eriod in nude mice bearing SCLC xenografts. The microspheres containin g BW2258U89 strongly inhibited SCLC growth in vivo. A radioimmunoassay was developed for the GRP receptor antagonists and the rabbit antiser um cross-reacted totally with BW2258U89 or BW1023U90. BW2258U89 immuno reactivity (5 nM) was detected in the plasma of nude mice containing t he microspheres after 1 week. These data suggest that GRP receptor ant agonists bind to receptors on SCLC tumors. Copyright (C) 1996 Elsevier Science Inc.