title: Growth inhibition of experimental pancreatic cancers and sustained reduction in epidermal growth factor receptors during therapy with hormonal peptide analogs.
abstract: Reduction in receptors for epidermal growth factor (EGF) in cancers appears to be one of the principal mechanisms through which peptide hormone analogs can inhibit tumor growth. In this study, hamsters with nitrosamine-induced pancreatic cancers were treated for 8 weeks with bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095, somatostatin analog RC-160 or the luteinizing hormone-releasing hormone antagonist Cetrorelix, using sustained delivery systems releasing 20, 35 and 20 microg analog/ day respectively. To establish the pattern of changes in the number and affinity of EGF receptors on tumors, groups of animals were sacrificed at regular intervals during therapy. Chronic treatment with RC-3095 or Cetrorelix resulted in an early (day 10) and sustained reduction (71% or 69% respectively) in EGF receptors on pancreatic tumors. In contrast, RC-160 decreased receptor concentration by 60% only after 20 days. Among the histological characteristics of proliferation, the decrease in argyrophilic nucleolar organizer regions, but not apoptotic and mitotic indices, showed a correlation with the fall in EGF receptors. The concentration of the receptors returned to the control level 4 days after cessation of chronic treatment with RC-3095. The effect of single injections of RC-3095, RC-160 and Cetrorelix on EGF receptors was also investigated. RC-160 decreased the number of EGF receptors on pancreatic cancers by 31% 3 h after administration, but the receptors had returned to normal level at 6 h. RC-3095 and Cetrorelix caused a 67% and 59% decline, respectively, in EGF receptors only 6 h after injection and the concentration of receptors remained low for 24 h. Thus, the pattern of downregulation of EGF receptors in pancreatic cancers appears to depend on the peptide used for therapy. Since the antitumor effect may be the result of the fall in EGF receptors in cancers, information on the time course of changes in these receptors during treatment with these analogs may lead to an improvement in therapeutic regimens.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, VA Medical Center, New Orleans, Louisiana 70112-1262, USA.
authors.forename: K
authors.initials: K
authors.lastname: Szepesházi
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: J M
authors.initials: JM
authors.lastname: Arencibia
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: M
authors.initials: M
authors.lastname: Vadillo-Buenfil
authors.forename: E
authors.initials: E
authors.lastname: Rodriguez-Martin
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006224:Cricetinae; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013006:Growth Hormone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008647:Mesocricetus; D008940:Mitotic Index / Q000187:drug effects; D009697:Nucleolus Organizer Region / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D010446:Peptide Fragments; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D007986:Luteinizing Hormone; D013006:Growth Hormone; D066246:ErbB Receptors; C062876:cetrorelix; D001839:Bombesin