Keller Gunhild, Schally Andrew V, Gaiser Timo, Nagy Attila, Baker Benjamin, Halmos Gabor, Engel Jörg B
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112-1262, USA.
Clin Cancer Res. 2005 Aug 1;11(15):5549-57. doi: 10.1158/1078-0432.CCR-04-2464.
To determine the expression of luteinizing hormone releasing hormone (LHRH) receptors in specimens and cell lines of human renal cell carcinoma (RCC) and to evaluate the antitumor efficacy of targeted therapy with a cytotoxic analogue of LHRH, AN-207, in vivo. AN-207, consisting of [D-Lys(6)] LHRH linked to a cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201), binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors.
The expression of LHRH receptors was investigated in 28 surgically removed specimens of human renal cell carcinoma (RCC) by immunohistochemistry and in three human RCC cell lines A-498, ACHN, and 786-0 by radioreceptor assays, Western immunoblotting, and reverse transcription-PCR analysis. Antitumor efficacy of AN-207 was examined in experimental models of these cell lines.
Positive staining for LHRH receptors was found in all (28 of 28) of the examined human RCC specimens. mRNA for LHRH receptor, receptor protein, and LHRH binding sites were detected in all three cell lines. AN-207 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 xenografts in vivo producing a 67.8% to 73.8% decrease in tumor volume and a 62.2% to 77.3% reduction in tumor weight. Nontargeted cytotoxic radical AN-201 had no significant antitumor effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed tumor inhibitory effects of AN-207.
Our findings indicate that LHRH receptors are expressed in human RCC specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogues.
确定促黄体生成素释放激素（LHRH）受体在人肾细胞癌（RCC）标本和细胞系中的表达，并评估用LHRH细胞毒性类似物AN - 207进行靶向治疗在体内的抗肿瘤疗效。AN - 207由与细胞毒性基团2 - 吡咯啉阿霉素（AN - 201）相连的[D - Lys(6)]LHRH组成，它与LHRH受体具有高亲和力，可靶向作用于表达这些受体的肿瘤。
通过免疫组织化学研究28例手术切除的人肾细胞癌（RCC）标本中LHRH受体的表达，并通过放射受体分析、Western免疫印迹和逆转录 - PCR分析研究三种人RCC细胞系A - 498、ACHN和786 - 0中LHRH受体的表达。在这些细胞系的实验模型中检测AN - 207的抗肿瘤疗效。
在所检测的所有（28例中的28例）人RCC标本中均发现LHRH受体阳性染色。在所有三种细胞系中均检测到LHRH受体的mRNA、受体蛋白和LHRH结合位点。AN - 207在体内显著（P < 0.05）抑制A - 498、ACHN和786 - 0异种移植物的生长，使肿瘤体积减少67.8%至73.8%，肿瘤重量减少62.2%至77.3%。非靶向细胞毒性基团AN - 201无显著抗肿瘤作用。过量的LHRH激动剂地加瑞克阻断LHRH受体可抑制AN - 207的肿瘤抑制作用。
我们的研究结果表明，LHRH受体在人RCC标本中表达，可用于细胞毒性LHRH类似物的靶向化疗。
