Bajo Ana M, Schally Andrew V, Halmos Gabor, Nagy Attila
Endocrine Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA.
Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3742-8.
The receptors for luteinizing hormone-releasing hormone receptor (LHRH-R) are found in >50% of human breast cancers. Doxorubicin (DOX) was linked to [D-Lys(6)]LHRH to form a cytotoxic conjugate, AN-152, which can be targeted to tumor cells expressing LHRH-R. We evaluated the effects of AN-152 on the estrogen-independent, DOX-resistant human mammary carcinoma line MX-1, xenografted into nude mice.
Nude mice bearing MX-1 tumors were administered five i.v. injections of AN-152 or DOX at doses equivalent to 3 mg/kg DOX. Tumor growth was followed, and changes in the expression of LHRH-R on tumors were evaluated by radioreceptor assays, reverse transcription-PCR, and Western blotting. The effects of AN-152 on the expression of human epidermal growth factor receptor (HER)-2 were investigated. Because LHRH-R are coupled to various G proteins, which are involved in mitogenic signaling, we determined the outcome of treatment with AN-152 on the levels of mRNA for different G proteins.
Treatment with AN-152 significantly (P < 0.05) decreased the final tumor volume to 978.56 +/- 176.85 mm(3), compared with the control tumors, which measured 2837.38 +/- 515.38 mm(3). Tumor doubling time was likewise significantly (P < 0.05) extended by AN-152 to 12.01 +/- 1.99 days from 6.45 +/- 0.36 days for the controls. Therapy with AN-152, but not with DOX, resulted in a significant decrease of LHRH-R levels on MX-1 tumors. The expression of mRNAs for HER-2, HER-3, Galpha(i2), and Galpha(11) and the levels of HER-2 and HER-3 proteins were also significantly reduced by AN-152.
Cytotoxic LHRH analogue AN-152 could be considered for targeted chemotherapy of DOX-resistant breast cancers expressing LHRH-R.
在超过50%的人类乳腺癌中发现了促黄体生成激素释放激素受体（LHRH-R）。阿霉素（DOX）与[D-赖氨酸（6）]LHRH连接形成细胞毒性偶联物AN-152，其可靶向作用于表达LHRH-R的肿瘤细胞。我们评估了AN-152对移植到裸鼠体内的雌激素非依赖性、阿霉素耐药的人乳腺癌细胞系MX-1的影响。
给携带MX-1肿瘤的裸鼠静脉注射5次AN-152或阿霉素，剂量相当于3mg/kg阿霉素。跟踪肿瘤生长情况，通过放射受体分析、逆转录PCR和蛋白质印迹法评估肿瘤上LHRH-R表达的变化。研究了AN-152对人表皮生长因子受体（HER）-2表达的影响。由于LHRH-R与多种G蛋白偶联，这些G蛋白参与有丝分裂信号传导，我们确定了用AN-152治疗对不同G蛋白mRNA水平的影响。
与对照肿瘤（体积为2837.38±515.38mm³）相比，用AN-152治疗显著（P<0.05）降低了最终肿瘤体积至978.56±176.85mm³。肿瘤倍增时间同样显著（P<0.05）延长，AN-152使其从对照的6.45±0.36天延长至12.01±1.99天。用AN-152治疗而非阿霉素治疗导致MX-1肿瘤上LHRH-R水平显著降低。AN-152还显著降低了HER-2、HER-3、Gα（i2）和Gα（11）的mRNA表达以及HER-2和HER-3蛋白的水平。
细胞毒性LHRH类似物AN-152可考虑用于对表达LHRH-R的阿霉素耐药乳腺癌进行靶向化疗。
