Nagy Attila, Schally Andrew V
Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Biol Reprod. 2005 Nov;73(5):851-9. doi: 10.1095/biolreprod.105.043489. Epub 2005 Jul 20.
Targeted chemotherapy is a modern approach aimed at increasing the efficacy of systemic chemotherapy and reducing its side effects. The peptide receptors expressed primarily on cancerous cells can serve as targets for a selective destruction of malignant tumors. Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens. Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule. To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys6]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX). In addition, we designed and synthesized a highly active derivative of DOX, 2-pyrrolino-DOX (AN-201), which is 500-1000 times more potent than DOX in vitro. AN-201 is active against tumors resistant to DOX, and noncardiotoxic. As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys6]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207. Both AN-152 and AN-207 can effectively inhibit the growth of LHRH receptor-positive human breast, ovarian, endometrial, and prostate cancers xenografted into nude mice. DOX-containing cytotoxic LHRH analog AN-152 is scheduled for clinical phase I/IIa trials in patients with advanced ovarian and breast cancers in 2005.
靶向化疗是一种旨在提高全身化疗疗效并减少其副作用的现代方法。主要在癌细胞上表达的肽受体可作为选择性破坏恶性肿瘤的靶点。在52%的人类乳腺癌、约80%的人类卵巢癌和子宫内膜癌以及86%的人类前列腺癌标本中发现了促黄体生成素释放激素（LHRH，在基因组和微阵列数据库中现称为GNRH1）的结合位点。由于LHRH受体在大多数正常组织中不表达，它们代表了用与LHRH载体分子相连的抗肿瘤药物进行癌症化疗的特定靶点。为了测试基于LHRH类似物的靶向化疗的疗效，我们最近开发了一种LHRH细胞毒性类似物，命名为AN - 152，它由[D - Lys6]LHRH与最广泛使用的化疗药物之一阿霉素（DOX）共价连接而成。此外，我们设计并合成了一种阿霉素的高活性衍生物，2 - 吡咯啉 - 阿霉素（AN - 201），其在体外的效力比阿霉素高500 - 1000倍。AN - 201对阿霉素耐药的肿瘤有活性，且无心脏毒性。与阿霉素一样，AN - 201与载体肽[D - Lys6]LHRH偶联形成一种超活性靶向细胞毒性LHRH类似物AN - 207。AN - 152和AN - 207都能有效抑制移植到裸鼠体内的LHRH受体阳性的人类乳腺癌、卵巢癌、子宫内膜癌和前列腺癌的生长。含阿霉素的细胞毒性LHRH类似物AN - 152计划于2005年在晚期卵巢癌和乳腺癌患者中进行临床I/IIa期试验。
