Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice
Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice
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DOI：
10.1023/a:1006352401912
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发表时间：
2000-02-01
影响因子：
3.8
通讯作者：
Groot, K
中科院分区：
文献类型：
--
作者：
Kahán, Z;Nagy, A;Groot, K
受体靶向化疗比常规化疗毒副作用小，疗效高。促黄体生成激素释放激素（LH-RH）的受体存在于约50%的人类乳腺癌中。将高效细胞毒性自由基2-吡咯啉多柔比星（AN-201）与激动剂类似物[D-Lys（6）]LH-RH连接以形成细胞毒性LH-RH类似物AN-207。我们评估了AN-207是否可以靶向非肿瘤依赖性MDA-MB-231人乳腺癌。对携带MDA-MB-231肿瘤的裸鼠静脉注射250 nmol/kg剂量的细胞毒性自由基AN-201、细胞毒性LH-RH类似物AN-207、AN-201和载体[D-Lys（6）]LH-RH的未缀合混合物、单独的[D-Lys（6）]LH-RH和载体（对照）。给予单剂量AN-207的动物中MDA-MB-231肿瘤的生长在注射后3周被显著抑制（p = 0.01），而所有其他组中的肿瘤稳定生长。所有的细胞毒性化合物产生白细胞减少症，但最强的淋巴细胞抑制引起的细胞毒性自由基AN-201。治疗3周后，通过RT-PCR证明所有组中存在LH-RH受体的mRNA，放射受体测定证明对照动物和用AN-201、单独的载体肽或与AN-201组合治疗的动物的肿瘤细胞膜上存在LH-RH的高亲和力结合位点。在该时间点，结合测定未揭示用AN-207处理的肿瘤中膜蛋白的表达，但在施用AN-207后60天，在MDA-MB-231肿瘤中再次发现高亲和力LH-RH结合位点。这些结果表明，细胞毒性LH-RH类似物AN-207可用于表达LH-RH受体的乳腺癌的受体靶向化疗。
Receptor targeted chemotherapy is less toxic and more effective than conventional chemotherapy. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast cancers. Highly potent cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) was linked to the agonistic analog [D-Lys(6)]LH-RH to form cytotoxic LH-RH analog AN-207. We evaluated whether AN-207 could be targeted to the hormone-independent MDA-MB-231 human breast cancers. Nude mice bearing MDA-MB-231 tumors were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic LH-RH analog AN-207, the unconjugated mixture of AN-201 and carrier [D-Lys(6)]LH-RH, [D-Lys(6)]LH-RH alone and vehicle (control). The growth of MDA-MB-231 tumors in animals given a single dose of AN-207 was inhibited significantly (p = 0.01) for 3 weeks after injection, whereas tumors in all the other groups grew steadily. All cytotoxic compounds produced leukopenia, but the strongest lymphocyte suppression was caused by cytotoxic radical AN-201. Three weeks after treatment, the presence of mRNA for LH-RH receptors was demonstrated by RT-PCR in all the groups and radioreceptor assays demonstrated high-affinity binding sites for LH-RH on tumor cell membranes of control animals and those treated with AN-201, the carrier peptide alone or in combination with AN-201. At this time point binding assays did not reveal the expression of membrane proteins in tumors treated with AN-207, but 60 days after administration of AN-207, high affinity LH-RH binding sites were found again in MDA-MB-231 tumors. These results indicate that cytotoxic LH-RH analog AN-207 could be utilized for receptor targeted chemotherapy of breast cancers expressing receptors for LH-RH.