Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers.

Abstract

We developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin (BN)-like carrier peptide is conjugated to 2-pyrrolino doxorubicin (AN-201). Human prostate cancers express high levels of receptors for BN/gastrin releasing peptide (GRP) that can be used for targeted chemotherapy. The effects of targeted chemotherapy with cytotoxic BN analogue AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human prostate cancers. Intraosseous growth of C4-2 tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and Bax protein was determined by Western blot analysis. Targeted analog AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b prostate cancers by 81% to 91% compared to controls, while cytotoxic radical AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate tumors were significantly reduced. In LuCaP-35 tumors administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215. High affinity receptors for BN/GRP and their m-RNA were detected on membranes of all 4 tumor models. Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. The presence of BN/GRP receptors on primary and metastatic prostate cancers makes possible targeted chemotherapy with AN-215 for the treatment of this malignancy.

• Authors: Anton Stangelberger, Andrew V Schally, Markus Letsch, Karoly Szepeshazi, Attila Nagy, Gabor Halmos, Celia A Kanashiro, Eva Corey, Robert Vessella
• Journal: International journal of cancer (Int J Cancer) Vol. 118 Issue 1 Pg. 222-9 (Jan 01 2006) ISSN: 0020-7136 [Print] United States
• PMID: 16003723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2005 Wiley-Liss, Inc.

Chemical References

• AN 215
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Bombesin
• Doxorubicin
• Bombesin

Topics

• Animals
• Apoptosis (drug effects)
• Bombesin (analogs & derivatives, pharmacology)
• Bone Neoplasms (pathology)
• Cell Proliferation (drug effects)
• Doxorubicin (analogs & derivatives, pharmacology)
• Gene Expression Profiling
• Humans
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (pathology)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Receptors, Bombesin (drug effects, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Transplantation, Heterologous