title: BW 1023U90: a new GRP receptor antagonist for small-cell lung cancer cells.
abstract: Gastrin-releasing peptide (GRP) receptor antagonists were synthesized and their ability to interact with small-cell lung cancer (SCLC) cells determined. [125I] BW1023U90, bound with high affinity (Kd = 2 nM) to a single class of sites (Bmax = 55 fmol/mg protein) using SCLC cell line NCI-H345. [125I] BW1023U90 binding was time dependent and reversible even at 37 degrees C as the ligand was minimally internalized. Specific [125I] BW1023U90 binding was inhibited with high affinity by GRP as well as bombesin (BB) but not neuromedin B (NMB). BW1023U90 inhibited the ability of BB to elevate cytosolic Ca2+ and increase the growth of SCLC cells. A BW1023U90 analogue, BW2258U89 (10 micrograms/day, SC) slowed SCLC xenograft format on in nude mice and [125I] BW 1023U90 localized 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 period in nude mice bearing SCLC xenografts. The microspheres containing BW2258U89 strongly inhibited SCLC growth in vivo. A radioimmunoassay was developed for the GRP receptor antagonists and the rabbit antiserum cross-reacted totally with BW2258U89 or BW1023U90. BW2258U89 immunoreactivity (5 nM) was detected in the plasma of nude mice containing the microspheres after 1 week. These data suggest that GRP receptor antagonists bind to receptors on SCLC tumors.
authors.affiliation: National Cancer Institute, Biomarkers and Prevention Research Branch, Rockville, MD 20850, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Moody
authors.forename: R
authors.initials: R
authors.lastname: Venugopal
authors.forename: V
authors.initials: V
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Gozes
authors.forename: J
authors.initials: J
authors.lastname: McDermed
authors.forename: J J
authors.initials: JJ
authors.lastname: Leban
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019886:Gastrin-Releasing Peptide; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C104867:BW 1023U90; D009842:Oligopeptides; D010455:Peptides; D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide