Chatzistamou L, Schally A V, Nagy A, Armatis P, Szepeshazi K, Halmos G
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Clin Cancer Res. 2000 Oct;6(10):4158-65.
A highly potent derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201), was linked to [D-Lys6]luteinizing hormone-releasing hormone (LH-RH) to form a cytotoxic analogue, AN-207, that can be targeted to LH-RH receptors. The effects of AN-207 were investigated in MDA-MB-435 human estrogen-independent breast carcinomas, which express LH-RH receptors. In experiment 1, nude mice bearing orthotopically implanted tumors received a single i.v. injection of AN-207, AN-201, or the carrier at 250 nmol/kg. Five weeks after administration of AN-207, tumor volume was significantly decreased by 66% (P < 0.001) and tumor burden by 71% (P < 0.05) as compared with controls, but no significant effects occurred in other groups. Six of eight (75%) control animals and 37.5% of mice treated with AN-201 developed metastases in the lymph nodes, whereas no lymphatic spread was found in any of the mice that received injections of AN-207. The antitumor effect of AN-207 could be partially blocked by pretreatment of the tumor-bearing mice with high doses of agonist [D-Trp6]LH-RH, which suggests that AN-207 acts on LH-RH receptors on tumors. The mortality due to toxicity was 25% in the group receiving AN-201 and 12.5% in the AN-207-treated group. Radioligand binding assays revealed the presence of high-affinity binding sites for LH-RH on tumor membranes, and mRNA for LH-RH receptors was demonstrated by reverse transcription-PCR. In experiment 2, two i.v. injections of AN-207 or AN-201 at 150 nmol/kg were given on days 0 and 28 to mice bearing orthotopic xenografts of MDA-MB-435. The outcome of the treatment was similar to that observed in experiment 1, but without any toxicity-related deaths. Tumor growth inhibition and prevention of metastatic disease suggest that cytotoxic LH-RH analogue AN-207 could be considered for the treatment of human estrogen-independent breast cancers expressing receptors for LH-RH.
阿霉素的一种高效衍生物2-吡咯啉阿霉素（AN - 201）与[D - Lys6]促黄体激素释放激素（LH - RH）连接，形成一种细胞毒性类似物AN - 207，它能够靶向作用于LH - RH受体。在表达LH - RH受体的MDA - MB - 435人雌激素非依赖性乳腺癌中研究了AN - 207的作用。在实验1中，原位植入肿瘤的裸鼠接受250 nmol/kg的AN - 207、AN - 201或载体的单次静脉注射。给予AN - 207五周后，与对照组相比，肿瘤体积显著减小66%（P < 0.001），肿瘤负荷降低71%（P < 0.05），但其他组未出现显著效果。八只（75%）对照动物中有六只以及37.5%接受AN - 201治疗的小鼠出现淋巴结转移，而接受AN - 207注射的小鼠中未发现任何淋巴转移。用高剂量激动剂[D - Trp6]LH - RH对荷瘤小鼠进行预处理可部分阻断AN - 207的抗肿瘤作用，这表明AN - 207作用于肿瘤上的LH - RH受体。接受AN - 201治疗组的毒性死亡率为25%，接受AN - 207治疗组为12.5%。放射性配体结合分析显示肿瘤细胞膜上存在LH - RH的高亲和力结合位点，通过逆转录 - PCR证实了LH - RH受体的mRNA。在实验2中，于第0天和第28天对原位移植MDA - MB - 435异种移植物的小鼠静脉注射两次150 nmol/kg的AN - 207或AN - 201。治疗结果与实验1中观察到的相似，但未出现任何与毒性相关的死亡。肿瘤生长抑制和转移性疾病的预防表明，细胞毒性LH - RH类似物AN - 207可考虑用于治疗表达LH - RH受体的人雌激素非依赖性乳腺癌。
