Gründker Carsten, Völker Peter, Griesinger Frank, Ramaswamy Annette, Nagy Attila, Schally Andrew V, Emons Günter
Departments of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
Am J Obstet Gynecol. 2002 Sep;187(3):528-37. doi: 10.1067/mob.2002.124278.
Most human endometrial and ovarian cancers express receptors for luteinizing hormone- releasing hormone. These receptors can be used for targeted chemotherapy with cytotoxic luteinizing hormone-releasing hormone analogs such as AN-152, in which doxorubicin is linked to [D-Lys(6)]luteinizing hormone-releasing hormone.
The antitumor effects of doxorubicin and AN-152 were assessed in vivo in human luteinizing hormone-releasing hormone receptor-positive HEC-1B endometrial cancers and NIH:OVCAR-3 ovarian cancers and in the luteinizing hormone-releasing hormone receptor-negative SK-OV-3 ovarian line. Nude mice bearing these tumors subcutaneously were injected intravenously with saline solution (control), AN-152, or doxorubicin at equimolar doses. Luteinizing hormone-releasing hormone receptor expression in tumors and specimens of human reproductive (n = 5) and nonreproductive (n = 15) normal tissues and in hematopoietic stem cells were analyzed with reverse transcriptase-polymerase chain reaction and radioligand binding assay.
The tumor volumes of luteinizing hormone-releasing hormone receptor-positive HEC-1B and NIH:OVCAR-3 cancers were reduced significantly (P <.001) 1 week after treatment with AN-152 at 700 nmol/20 g or at 300 nmol/20 g. No toxic side effects were observed. Treatment with doxorubicin arrested tumor growth but did not reduce tumor volume. Doxorubicin at 700 nmol/20 g caused a high mortality rate and at 300 nmol/20 g (8.7 mg/kg) caused a loss of body weight, but no deaths occurred. The growth of luteinizing hormone-releasing hormone receptor-negative SK-OV-3 cancers was not affected by AN-152. Normal human nonreproductive tissues, hematopoietic stem cells, and vaginal tissue did not express luteinizing hormone-releasing hormone receptors, but luteinizing hormone-releasing hormone receptors were found in the ovary, fallopian tube, cervix, endometrium, and myometrium.
Targeted chemotherapeutic luteinizing hormone-releasing hormone analog AN-152 is more effective and less toxic than cytotoxic radical doxorubicin on luteinizing hormone-releasing hormone receptor-positive tumors. AN-152 could be considered for targeted chemotherapy in patients with ovarian or endometrial cancers.
大多数人类子宫内膜癌和卵巢癌表达促黄体生成素释放激素受体。这些受体可用于用细胞毒性促黄体生成素释放激素类似物进行靶向化疗，如AN - 152，其中阿霉素与[D - Lys(6)]促黄体生成素释放激素相连。
在人促黄体生成素释放激素受体阳性的HEC - 1B子宫内膜癌和NIH:OVCAR - 3卵巢癌以及促黄体生成素释放激素受体阴性的SK - OV - 3卵巢癌细胞系中，在体内评估阿霉素和AN - 152的抗肿瘤作用。将携带这些肿瘤的裸鼠皮下注射等摩尔剂量的生理盐水溶液（对照）、AN - 152或阿霉素。用逆转录聚合酶链反应和放射性配体结合试验分析肿瘤、人类生殖（n = 5）和非生殖（n = 15）正常组织标本以及造血干细胞中促黄体生成素释放激素受体的表达。
用700 nmol/20 g或300 nmol/20 g的AN - 152治疗1周后，促黄体生成素释放激素受体阳性的HEC - 1B和NIH:OVCAR - 3癌的肿瘤体积显著减小（P <.001）。未观察到毒性副作用。阿霉素治疗可抑制肿瘤生长，但未减小肿瘤体积。700 nmol/20 g的阿霉素导致高死亡率，300 nmol/20 g（8.7 mg/kg）导致体重减轻，但未发生死亡。促黄体生成素释放激素受体阴性的SK - OV - 3癌的生长不受AN - 152影响。正常人类非生殖组织、造血干细胞和阴道组织不表达促黄体生成素释放激素受体，但在卵巢、输卵管、宫颈、子宫内膜和子宫肌层中发现了促黄体生成素释放激素受体。
靶向化疗促黄体生成素释放激素类似物AN - 152在促黄体生成素释放激素受体阳性肿瘤上比细胞毒性自由基阿霉素更有效且毒性更小。AN - 152可考虑用于卵巢癌或子宫内膜癌患者的靶向化疗。
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