Inhibition of mutant p53 expression and growth of DMS-153 small cell lung carcinoma by antagonists of growth hormone-releasing hormone and bombesin.
We investigated the effects of growth hormone-releasing hormone (GHRH) antagonists, JV-1-65 and JV-1-63, and bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on DMS-153 human small cell lung carcinoma xenografted into nude mice. Treatment with 10 microg/day JV-1-65 or RC-3940-II decreased tumor volume by 28% (P < 0.05) and 77% (P < 0.01), respectively, after 42 days compared with controls. Combination of JV-1-65 and RC-3940-II induced the greatest inhibition of tumor proliferation (95%; P < 0.01), suggesting a synergism. Western blotting showed that the antitumor effects of these antagonists were associated with inhibition of the expression of the mutant tumor suppressor protein p53 (Tp53). Mutation was detected by sequence analysis of the p53 gene at codon 155: ACC [Thr] --> CCC [Pro]. Combination of JV-1-65 and RC-3940-II decreased the levels of mutant p53 protein by 42% (P < 0.01) compared with controls. JV-1-65, JV-1-63, and RC-3940-II, given singly, reduced mutant p53 protein expression by 18-24% (P < 0.05). Serum insulin-like growth factor (IGF)-I levels were diminished in animals receiving GHRH antagonists. mRNA levels for IGF-II, IGF receptor-I, GRP receptor, and EGF receptor in tumors were significantly decreased by combined treatment with JV-1-65 and RC-3940-II. DMS-153 tumors expressed mRNAs for GHRH and GHRH receptor splice variants 1 and 2, suggesting that GHRH could be an autocrine growth factor. Proliferation of DMS-153 cells in vitro was stimulated by GRP and IGF-II and inhibited by JV-1-65. This study indicates that GHRH antagonists and BN/GRP antagonist inhibit the growth of DMS-153 small cell lung carcinoma concomitantly with the expression of mutant Tp53, which might uncouple the signal transduction pathways for cell growth stimulation.
Kanashiro
Celia A
CA
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, 70112-2699, USA.
Schally
Andrew V
AV
Groot
Kate
K
Armatis
Patricia
P
Bernardino
Andrea L F
AL
Varga
Jozsef L
JL
D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016158:Genes, p53; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D018076:DNA, Complementary; D010446:Peptide Fragments; D012334:RNA, Neoplasm; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; D001839:Bombesin