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Targeted chemotherapy with cytotoxic bombesin analogue AN‐215 inhibits growth of experimental human prostate cancers
Author(s) -
Stangelberger Anton,
Schally Andrew V.,
Letsch Markus,
Szepeshazi Karoly,
Nagy Attila,
Halmos Gabor,
Kanashiro Celia A.,
Corey Eva,
Vessella Robert
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21292
Subject(s) - bombesin , gastrin releasing peptide , cytotoxic t cell , prostate cancer , receptor , medicine , cancer research , prostate , doxorubicin , chemotherapy , growth inhibition , apoptosis , cancer , pharmacology , chemistry , in vitro , biochemistry , neuropeptide
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.