Synergistic effects of bombesin and epidermal growth factor on cancers.
Bombesin and gastrin-releasing peptide act as autocrine mitogens in various cancers. Bombesin antagonist RC-3095 inhibited growth in some cancers and slowed the progression of premalignant lesions, possibly by down-regulating epidermal growth factor (EGF) receptors. Since the EGF receptor mitogen response involves tyrosine kinase stimulation, we tested the hypotheses that bombesin stimulates, and RC-3095 inhibits, phosphorylation; EGF and bombesin promote the phosphorylation of the same substrates; and EGF and bombesin act synergistically on phosphorylation. Therefore, in vitro assays for phosphorylation were performed in the presence or absence of EGF, bombesin, RC-3095, and combinations in samples derived from tumor, tissue surrounding tumor, cell lines, and normal and transforming tissue derived from the 9,10-dimethyl-1,2-benzanthracene-induced squamous cell lesions of the hamster cheek pouch. Bombesin increased, and RC-3095 decreased, phosphorylation in these samples. In the human hepatoma sample and surrounding tissue, these ligands altered the phosphorylation of the same substrates affected by EGF. EGF and bombesin stimulated phosphorylation synergistically in the hamster samples and the hepatoma. Bombesin-induced phosphorylation was greater in tissue surrounding the hepatoma, whereas RC-3095 was more effective in inhibiting phosphorylation in the hepatoma itself. This cancer, therefore, could be endogenously stimulated by gastrin-releasing peptide. These observations support the hypothesis that bombesin stimulates growth of tissues and tumors by amplifying the phosphorylation response to EGF. The growth inhibitory response to RC-3095, or other bombesin analogues, of individual tumors may be prognosed by in vitro phosphorylation assays using the samples from the patient's tumor.
Liebow
C
C
Department of Oral Surgery, School of Dental Medicine, State University of New York at Buffalo 14214.
Crean
D H
DH
Lee
M T
MT
Kamer
A R
AR
Mang
T S
TS
Schally
A V
AV
D000818:Animals; D001839:Bombesin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000008:administration & dosage*; D008297:Male; D008647:Mesocricetus; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation
D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D004815:Epidermal Growth Factor; D001839:Bombesin