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: S Westphalen, G Kotulla, F Kaiser, W Krauss, G Werning, H P Elsasser, A Nagy, K D Schulz, C Grundker, A V Schally, G Emons
• Journal: International journal of oncology (Int J Oncol) Vol. 17 Issue 5 Pg. 1063-9 (Nov 2000) ISSN: 1019-6439 [Print] Greece
• PMID: 11029513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Neoplasm Proteins
• Receptors, LHRH
• LHRH, lysine(6)-doxorubicin
• Gonadotropin-Releasing Hormone
• Doxorubicin

Topics

• Adenocarcinoma (pathology)
• Adenocarcinoma, Mucinous (pathology)
• Adenocarcinoma, Papillary (pathology)
• Antineoplastic Agents (metabolism, pharmacology)
• Biological Transport
• Carcinoma, Endometrioid (pathology)
• Cell Division (drug effects)
• Cell Nucleus (metabolism)
• Cystadenocarcinoma, Serous (pathology)
• Doxorubicin (analogs & derivatives, metabolism, pharmacology)
• Drug Screening Assays, Antitumor
• Endometrial Neoplasms (pathology)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology)
• Humans
• Microscopy, Confocal
• Neoplasm Proteins (drug effects, physiology)
• Neoplasms, Hormone-Dependent (pathology)
• Ovarian Neoplasms (pathology)
• Receptors, LHRH (drug effects, physiology)
• Tumor Cells, Cultured (drug effects, pathology)