title: Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways.
abstract: BACKGROUND
  In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin-releasing peptide (BN/GRP) on PC-3 human prostate cancers.
  
  
  METHODS
  Nude mice implanted with PC-3 tumors received GHRH antagonists MZ-5-156 or JV-1-38, each at 20 microgram/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 microgram), BN/GRP antagonist RC-3940-II (10 microgram), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated.
  
  
  RESULTS
  JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum IGF-I concentration was lowered only in mice treated with JV-1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II.
  
  
  CONCLUSIONS
  The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen-independent prostate cancer.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana, USA.
authors.forename: A
authors.initials: A
authors.lastname: Plonowski
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: J L
authors.initials: JL
authors.lastname: Varga
authors.forename: Z
authors.initials: Z
authors.lastname: Rekasi
authors.forename: F
authors.initials: F
authors.lastname: Hebert
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: K
authors.initials: K
authors.lastname: Groot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001839:Bombesin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012334:RNA, Neoplasm / Q000737:chemistry / Q000302:isolation & purification; D011863:Radioimmunoassay; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017337:Sermorelin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D004273:DNA, Neoplasm; C411623:JV 1-38; C106656:MZ 5-156; D010446:Peptide Fragments; D012334:RNA, Neoplasm; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; D007334:Insulin-Like Growth Factor I; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D001839:Bombesin