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: Z Szereday, A V Schally, A Nagy, A Plonowski, A M Bajo, G Halmos, K Szepeshazi, K Groot
• Journal: British journal of cancer (Br J Cancer) Vol. 86 Issue 8 Pg. 1322-7 (Apr 22 2002) ISSN: 0007-0920 [Print] England
• PMID: 11953892 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2002 Cancer Research UK

Chemical References

• AN 215
• RNA, Messenger
• Receptors, Bombesin
• Doxorubicin
• Bombesin

Topics

• Animals
• Bombesin (adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Cell Division (drug effects)
• Doxorubicin (adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Mice
• Mice, Nude
• Neoplasm Transplantation
• RNA, Messenger (genetics, metabolism)
• Receptors, Bombesin (antagonists & inhibitors, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured