[Psi 13,14] bombesin analogues inhibit growth of small cell lung cancerin vitro and in vivo.
Bombesin/gastrin releasing peptide (BN/GRP) functions as an autocrine growth factor in small cell lung cancer (SCLC). Previously, this autocrine growth cycle was disrupted by a monoclonal antibody which binds to the carboxyl terminal of BN and neutralizes the peptide so that it is unable to interact with the BN/GRP receptor. Here a series of BN analogues were synthesized which have a reduced peptide bond near the carboxyl terminal. The analogues inhibited specific binding of 125I-GRP to SCLC cell line NCI-H345 in a dose-dependent manner and the analogue [D-Nal6, Psi13,14, Phe14] BN6-14 was approximately 6-fold more potent than was (Psi13,14, Leu14)BN with a 50% inhibition concentration value of 5 nM. [DNal6, Psi13,14, Phe14]BN6-14 and [Psi13,14, Leu14]BN had no effect on the cytosolic Ca2+ levels but antagonized the increase in cytosolic Ca2+ caused by 10 nM BN. [Psi13,14, Leu14]BN (1 microM) inhibited the growth of SCLC in vitro using a clonogenic assay by approximately 70% Also, injection of [Psi13,14, Leu14]BN (10 micrograms, s.c.) inhibited the growth of SCLC xenografts in nude mice in vivo by approximately 50%. These data suggest that the autocrine growth cycle of BN/GRP in SCLC may also be disrupted by peptide antagonists which bind to the BN receptor.
Mahmoud
S
S
Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
Staley
J
J
Taylor
J
J
Bogden
A
A
Moreau
J P
JP
Coy
D
D
Avis
I
I
Cuttitta
F
F
Mulshine
J L
JL
Moody
T W
TW
D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019886:Gastrin-Releasing Peptide; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000378:metabolism*; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D010455:Peptides; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; C067902:bombesin (6-14), Nal(6)-Psi(13,14)-Phe(14)-; C067901:bombesin, Psi(13,14)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D001839:Bombesin; D002118:Calcium