Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines

Int J Oncol. 2000 Nov;17(5):1063-9. doi: 10.3892/ijo.17.5.1063.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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