Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207

Jose M. Arencibia, Ana M. Bajo, Andrew V. Schally, Magdalena Krupa, Ioulia Chatzistamou, Attila Nagy

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 the in vivo growth 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.

Original languageEnglish (US)
Pages (from-to)949-956
Number of pages8
JournalAnti-Cancer Drugs
Volume13
Issue number9
DOIs
StatePublished - Oct 1 2002
Externally publishedYes

Keywords

  • Cytotoxic luteinizing hormone-releasing hormone analog
  • Ovarian cancer
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

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