title: Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines.
abstract: Eighty percent of human ovarian and endometrial cancers express receptors for luteinizing hormone-releasing hormone (LHRH). These receptors might be used for targeted chemotherapy with cytotoxic LHRH analogs such as AN-152, in which doxorubicin is linked to agonist carrier [D-Lys6]LHRH. The antiproliferative effects of doxorubicin and AN-152 were assessed in LHRH receptor-positive ovarian (EFO-21, EFO-27) and endometrial (HEC-1A, Ishikawa) cancer cell lines as well as in LHRH receptor negative ovarian SKOV-3 and endometrial MFE-296 lines. The mechanism of action of AN-152 was investigated by a blockage of receptors using an excess of the LHRH agonist [D-Trp6]LHRH. In some cases, confocal laser-scanning microscopy was used to visualize the accumulation of AN-152 or doxorubicin within the cells. In 3 of 4 LHRH receptor-positive cell lines (EFO-21, HEC-1A, Ishikawa) AN-152 was more effective than doxorubicin in inhibiting cell proliferation. The effect of AN-152 was shown to be receptor-mediated because it could be reduced by competitive blockade of the LHRH receptors with [D-Trp6]LHRH. In contrast, AN-152 was less active than doxorubicin in LHRH receptor-negative lines. Confocal laser-scanning microscopy showed an intranuclear accumulation of AN-152 and competitive inhibition thereof by [D-Trp6]LHRH in LHRH receptor-positive cell lines, but no intracellular accumulation of AN-152 could be detected in the receptor-negative SKOV-3 line. These results suggest a selective receptor-mediated action of AN-152 in receptor-positive cell lines.
authors.affiliation: Department of Gynecology and Obstetrics, Georg-August University Gottingen, 37075 Gottingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Westphalen
authors.forename: G
authors.initials: G
authors.lastname: Kotulla
authors.forename: F
authors.initials: F
authors.lastname: Kaiser
authors.forename: W
authors.initials: W
authors.lastname: Krauss
authors.forename: G
authors.initials: G
authors.lastname: Werning
authors.forename: H P
authors.initials: HP
authors.lastname: Elsasser
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: K D
authors.initials: KD
authors.lastname: Schulz
authors.forename: C
authors.initials: C
authors.lastname: Grundker
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: G
authors.initials: G
authors.lastname: Emons
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D002288:Adenocarcinoma, Mucinous / Q000473:pathology; D000231:Adenocarcinoma, Papillary / Q000473:pathology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D018269:Carcinoma, Endometrioid / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D011966:Receptors, LHRH / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin