title: Effective inhibition of experimental human ovarian cancers with a targeted cytotoxic bombesin analogue AN-215.
abstract: OBJECTIVE
  To determine whether the cytotoxic analogue of bombesin/gastrin-releasing peptide (GRP) AN-215 can inhibit the in vivo growth of four human ovarian cancer cell lines. AN-215 consists of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin linked to a bombesin antagonist carrier des-D-Tpi-RC-3095. This conjugate binds strongly to receptors for bombesin/GRP and can be targeted to tumors that express these receptors. Bombesin/GRP receptors are found in 77% of human ovarian cancer specimens.
  
  
  METHODS
  Nude mice bearing xenografts of ES-2, SKOV-3, OV-1063, and UCI-107 human ovarian carcinomas were treated with AN-215. The antitumor effects and the toxicity were determined. The expression of bombesin receptor subtypes was measured by reverse-transcriptase PCR analysis, and the presence of bombesin/GRP receptors was determined by radioligand binding assays.
  
  
  RESULTS
  AN-215 significantly (P < 0.05) inhibited growth of ES-2, OV-1063, and UCI-107 tumors, prevented the metastatic spread of ES-2 cancers, and prolonged the survival of nude mice bearing i.p. ES-2 xenografts. Cytotoxic radical AN-201, the unconjugated mixture of bombesin antagonist RC-3095 and AN-201 or RC-3095 alone had no significant effects. Blockade of bombesin/GRP receptors abolished the effect of AN-215. The expression of bombesin/GRP receptors was not changed after repeated treatment with AN-215.
  
  
  CONCLUSIONS
  Our findings indicate that targeted chemotherapy with cytotoxic bombesin/GRP analogue AN-215 can inhibit ovarian tumors, which express bombesin/GRP receptors. AN-215 might provide a new treatment modality for women with advanced ovarian carcinoma.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.forename: Gunhild
authors.initials: G
authors.lastname: Keller
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
authors.forename: Brian
authors.initials: B
authors.lastname: Hammann
authors.forename: Attila
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011869:Radioligand Assay; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C416531:AN 215; D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide; D004317:Doxorubicin; D001839:Bombesin