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

✍ Scribed by Anton Stangelberger; Andrew V. Schally; Markus Letsch; Karoly Szepeshazi; Attila Nagy; Gabor Halmos; Celia A. Kanashiro; Eva Corey; Robert Vessella

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 303 KB
• Volume: 118
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21292

✦ Synopsis

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 ^125^I‐[Tyr^4^]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. © 2005 Wiley‐Liss, Inc.