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

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-Lys ]LHRH. We investigated the effects of AN-207 and AN-201 on the 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-Lys ]LHRH, an unconjugated mixture of AN-201 and [D-Lys ]LHRH or vehicle. AN-207 caused a significant ( <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 ( <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 ( <0.05). The results indicate that cytotoxic LHRH analog AN-207 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.

• Authors: Jose M Arencibia, Ana M Bajo, Andrew V Schally, Magdalena Krupa, Ioulia Chatzistamou, Attila Nagy
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 13 Issue 9 Pg. 949-56 (Oct 2002) ISSN: 0959-4973 [Print] England
• PMID: 12394258 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Pyrroles
• RNA, Messenger
• Receptors, LHRH
• AN 204
• AN 207
• Gonadotropin-Releasing Hormone
• Doxorubicin
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Doxorubicin (analogs & derivatives, therapeutic use)
• Drug Evaluation, Preclinical
• ErbB Receptors (antagonists & inhibitors, biosynthesis)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, therapeutic use)
• Humans
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Ovarian Neoplasms (drug therapy, metabolism)
• Pyrroles (therapeutic use)
• RNA, Messenger (analysis)
• Receptor, ErbB-2 (antagonists & inhibitors, biosynthesis)
• Receptors, LHRH (antagonists & inhibitors, biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction
• Treatment Outcome
• Tumor Cells, Cultured