靶向细胞毒性促黄体生成素释放激素类似物AN-207对人实验性前列腺癌的抑制作用

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

作者信息

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

机构信息

Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112-1262, USA.

出版信息

Prostate. 2006 Feb 1;66(2):200-10. doi: 10.1002/pros.20335.

DOI:10.1002/pros.20335

PMID:16173040

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-Lys6] 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.

摘要

背景

人前列腺癌上的促黄体生成激素释放激素（LHRH）受体可用于用LHRH的细胞毒性类似物进行靶向化疗，例如AN - 207，它由与载体[D - Lys6]LHRH连接的超活性阿霉素衍生物2 - 吡咯啉阿霉素（AN - 201）组成。

方法

在移植到裸鼠体内的DU - 145雄激素非依赖性和LuCaP - 35雄激素敏感性人前列腺癌异种移植物中研究了AN - 207和AN - 201的作用。通过生存率、体重变化和白细胞计数评估毒性。通过放射受体分析和RT - PCR评估DU - 145和LuCaP - 35肿瘤上的LHRH受体。通过组织学以及Western Blot分析评估凋亡癌基因Bcl - 2和Bax来研究对凋亡和细胞增殖的影响。

结果

AN - 207显著抑制DU - 145肿瘤生长75%（P < 0.01），抑制LuCaP - 35人前列腺癌生长80%（P < 0.01），且毒性低于AN - 201。DU - 145和LuCaP - 35肿瘤上表达LHRH受体。用LHRH激动剂曲普瑞林阻断LHRH受体使AN - 207的作用失效。用AN - 207治疗而非AN - 201治疗可降低DU - 145肿瘤中的Bcl - 2/Bax比值以及LuCaP - 35肿瘤中的Bcl - 2，表明凋亡活性增加。在两种模型中，AN - 207而非AN - 201可降低细胞增殖。