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

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

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21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)222-229
Number of pages8
JournalInternational Journal of Cancer
Volume118
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

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Keywords

  • Androgen-dependent and -independent prostate cancer
  • Bax
  • Bcl-2
  • Cytotoxic bombesin analog

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Stangelberger, A., Schally, A. V., Letsch, M., Szepeshazi, K., Nagy, A., Halmos, G., Kanashiro, C. A., Corey, E., & Vessella, R. (2006). Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers. International Journal of Cancer, 118(1), 222-229. https://doi.org/10.1002/ijc.21292