title: Metabolic stability and tumor inhibition of bombesin/GRP receptor antagonists.
abstract: Small cell lung cancers (SCLC) synthesize and secrete bombesin/gastrin releasing peptide (BN/GRP). The autocrine growth cycle of BN/GRP in SCLC can be disrupted by BN/GRP receptor antagonists such as [Psi13,14]BN. Here several BN analogues were solid-phase synthesized and incubated with intact SCLC cells at 37 degrees C in RPMI medium in a time-course fashion (0-1080 minutes) to determine enzymatic stability. The proteolytic stability of the compounds was determined by subsequent HPLC analysis. The metabolic half-life ranged from 154 minutes to 1388 minutes for the six analogues studied. [Psi13,14]BN was found to be very stable to metabolic enzymes (T1/2 = 646 mm) and also inhibited SCLC xenograft formation in vivo in a dose-dependent manner. When [Psi13,14]BN was incubated with NCI-H345 cells, it inhibited 125I-GRP binding with an IC50 value of 30 nM. These data suggest that BN/GRP receptor antagonists such as [Psi13,14]BN may be useful for the treatment of SCLC.
authors.affiliation: Department of Pharmacology, University of Arizona, College of Medicine, Tucson 85724.
authors.forename: T P
authors.initials: TP
authors.lastname: Davis
authors.forename: S
authors.initials: S
authors.lastname: Crowell
authors.forename: J
authors.initials: J
authors.lastname: Taylor
authors.forename: D L
authors.initials: DL
authors.lastname: Clark
authors.forename: D
authors.initials: D
authors.lastname: Coy
authors.forename: J
authors.initials: J
authors.lastname: Staley
authors.forename: T W
authors.initials: TW
authors.lastname: Moody
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001839:Bombesin / Q000378:metabolism* / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D019886:Gastrin-Releasing Peptide; D006207:Half-Life; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000032:analysis / Q000037:antagonists & inhibitors*; D015290:Second Messenger Systems / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D019886:Gastrin-Releasing Peptide; D001839:Bombesin