Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207

Anton Stangelberger, Andrew V. Schally, Attila Nagy, Karoly Szepeshazi, Celia A. Kanashiro, Gabor Halmos

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LHRH) on human prostate cancers can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, which consists of superactive doxorubicin derivative 2-pyrrolino doxorubicin (AN-201) linked to carrier [D-Lys 6] LHRH. METHODS. The effects of AN-207 and AN-201 were investigated in DU-145 androgen independent and LuCaP-35 androgen sensitive human prostate cancers xenografted into nude mice. Toxicity was evaluated by survival rates, changes in body weights, and leukocyte counts. LHRH receptors on DU-145 and LuCaP-35 tumors were evaluated by radioreceptor assays and RT-PCR. The effects on apoptosis and cell proliferation were investigated by histology and evaluation of apoptotic oncogenes Bcl-2 and Bax by Western Blot analysis. RESULTS. AN-207 inhibited growth of DU-145 tumors significantly by 75% (P < 0.01) and LuCaP-35 human prostate cancers by 80% (P < 0.01), and was less toxic than AN-201. Receptors for LHRH were expressed on DU-145 and LuCaP-35 tumors. Blockade of LHRH receptors with LHRH agonist Triptorelin nullified the effects of AN-207. Treatment with AN-207, but not with AN-201, decreased Bcl-2/Bax ratio in DU-145 tumors and Bcl-2 in LuCaP-35 tumors indicating an increase in apoptotic activity. AN-207, but not AN-201, decreased cell proliferation in both models. CONCLUSIONS. Targeted chemotherapy with AN-207 could be considered for treatment of advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)200-210
Number of pages11
JournalProstate
Volume66
Issue number2
DOIs
StatePublished - Feb 1 2006
Externally publishedYes

Keywords

  • Cytotoxic LH-RH analog
  • LH-RH receptor
  • Prostate cancer
  • Targeted therapy

ASJC Scopus subject areas

  • Urology

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