Effective inhibition of experimental human ovarian cancers with a targeted cytotoxic bombesin analogue AN-215.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Jörg B Engel, Gunhild Keller, Andrew V Schally, Gabor Halmos, Brian Hammann, Attila Nagy
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 6 Pg. 2408-15 (Mar 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15788692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AN 215
• Receptors, Bombesin
• Gastrin-Releasing Peptide
• Doxorubicin
• Bombesin

Topics

• Animals
• Bombesin (analogs & derivatives, therapeutic use)
• Doxorubicin (analogs & derivatives, therapeutic use)
• Female
• Gastrin-Releasing Peptide (genetics, metabolism)
• Humans
• Mice
• Mice, Nude
• Ovarian Neoplasms (metabolism, pathology, prevention & control)
• Radioligand Assay
• Receptors, Bombesin (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays