title: Application of human pancreatic carcinoid BON cells for receptor-targeted drug development.
abstract: In our previous study, we found that several tumor cell lines displayed high receptor-specific binding affinity, one of which, the human pancreatic carcinoid BON cell line, demonstrates high affinity binding of the bombesin (BN) and somatostatin (SST) receptor-specific ligands. In the present study, BON cells, as a representative model, were further applied to evaluate various peptide analogs and cytotoxic receptor-targeted peptide conjugates. We observed quick ligand-receptor internalization in BON cells as well as high binding affinity. Furthermore, BON cells have high expression of multidrug resistance-associated genes (MDR1) and show camptothecin (CPT) resistance. Various receptor-specific cytotoxic conjugates were synthesized and evaluated in the BON cell model via in vitro and in vivo studies. We found that all the tested conjugates displayed potent antitumor ability in xenografts. Especially, the CPT conjugates, CPT-SST, and CPT-BN, are most likely to increase sensitivity to CPT-resistant BON cells. Our findings suggest that appropriately defined tumor cell lines may provide physiologically relevant cell-based evaluations of novel peptide analogs and receptor-targeted chemotherapeutics.
authors.affiliation: Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA. lsun@tulane.edu
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
authors.forename: Lynsie M
authors.initials: LM
authors.lastname: Morris
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.forename: L Vienna
authors.initials: LV
authors.lastname: Mackey
authors.forename: Juliana S
authors.initials: JS
authors.lastname: Leslie
authors.forename: Laura G
authors.initials: LG
authors.lastname: Franko-Tobin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.forename: Keith T
authors.initials: KT
authors.lastname: LePage
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001632:Bibenzyls / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001839:Bombesin / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D018004:Receptors, Bombesin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D004337:Drug Carriers; D008024:Ligands; D018004:Receptors, Bombesin; D011956:Receptors, Cell Surface; D017481:Receptors, Somatostatin; D013004:Somatostatin; C040105:combretastatin; D001839:Bombesin; D002166:Camptothecin