Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207
作者:
Jose Arencibia,
Ana Bajo,
Andrew Schally,
Magdalena Krupa,
Ioulia Chatzistamou,
Attila Nagy,
期刊:
Anti-Cancer Drugs
(OVID Available online 2002)
卷期:
Volume 13,
issue 9
页码: 949-956
ISSN:0959-4973
年代: 2002
出版商: OVID
关键词: Cytotoxic luteinizing hormone-releasing hormone analog;ovarian cancer;targeted chemotherapy
数据来源: OVID
摘要:
The receptors for luteinizing hormone-releasing hormone (LHRH) are found in 80% of human ovarian carcinomas. These receptors can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to [D-Lys6]LHRH. We investigated the effects of AN-207 and AN-201 on thein vivogrowth of LHRH receptor-positive ES-2 human ovarian cancers. The effects of the treatment on mRNA and protein levels of human epidermal growth factor (EGF) receptors (EGFR and HER-2) in ovarian tumors were determined by RT-PCR and immunoblotting. In Experiment 1, nude mice bearing ES-2 ovarian tumors were injected i.v. with 250 nmol/kg doses of AN-207, AN-201, the carrier [D-Lys6]LHRH, an unconjugated mixture of AN-201 and [D-Lys6]LHRH or vehicle. AN-207 caused a significant (p<0.01) 59.5% inhibition in tumor growth while its components were ineffective. In Experiment 2, mice with large ES-2 tumors were treated with AN-207 or AN-201 at 250 nmol/kg. Again, AN-207, but not AN-201, inhibited tumor growth. In Experiment 3, the site of action of AN-207 was investigated. The blockade of LHRH receptors with Cetrorelix partially suppressed the antitumor effect of AN-207. Treatment with AN-207 significantly (p<0.01) decreased the expression of mRNA for EGFR, and HER-2 by 27 and 34%, respectively, as compared to controls and reduced the receptor protein levels of EGFR and HER-2 by 35 and 36%, respectively (p<0.05). The results indicate that cytotoxic LHRH analog AN-207 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.
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