title: Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215.
abstract: Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas xenografted into nude mice. High affinity binding of AN-215 to U-87MG tumours was characterised by an IC(50) value of 4.0+/-0.1 nM, as determined by radioreceptor assays. mRNA analyses revealed the presence of mRNA for BN receptor subtypes 1 and 2. Treatment with AN-215 significantly (P<0.05) extended tumour doubling time from 4.54+/-0.2 days to 8.18+/-1.8 days and inhibited tumour growth as demonstrated by a 69.6% reduction in final tumour volume (P<0.001) and a 64.6% decrease in tumour weight as compared to controls. Cytotoxic radical AN-201 at the same dose was ineffective. The antitumour effect of AN-215 could be blocked by pretreatment with an excess of a bombesin antagonist, indicating that the action of this cytotoxic analogue is receptor-mediated. Our results suggest that patients with inoperable brain tumours such as malignant gliomas may benefit from targeted chemotherapy based on cytotoxic bombesin analogue AN-215.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Szereday
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: A
authors.initials: A
authors.lastname: Plonowski
authors.forename: A M
authors.initials: AM
authors.lastname: Bajo
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: K
authors.initials: K
authors.lastname: Szepeshazi
authors.forename: K
authors.initials: K
authors.lastname: Groot
mesh_terms: D000818:Animals; D001839:Bombesin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C416531:AN 215; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D004317:Doxorubicin; D001839:Bombesin