Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice

Am J Obstet Gynecol. 2002 Sep;187(3):528-37. doi: 10.1067/mob.2002.124278.


Objective: Most human endometrial and ovarian cancers express receptors for luteinizing hormone- releasing hormone. These receptors can be used for targeted chemotherapy with cytotoxic luteinizing hormone-releasing hormone analogs such as AN-152, in which doxorubicin is linked to [D-Lys(6)]luteinizing hormone-releasing hormone.

Study design: The antitumor effects of doxorubicin and AN-152 were assessed in vivo in human luteinizing hormone-releasing hormone receptor-positive HEC-1B endometrial cancers and NIH:OVCAR-3 ovarian cancers and in the luteinizing hormone-releasing hormone receptor-negative SK-OV-3 ovarian line. Nude mice bearing these tumors subcutaneously were injected intravenously with saline solution (control), AN-152, or doxorubicin at equimolar doses. Luteinizing hormone-releasing hormone receptor expression in tumors and specimens of human reproductive (n = 5) and nonreproductive (n = 15) normal tissues and in hematopoietic stem cells were analyzed with reverse transcriptase-polymerase chain reaction and radioligand binding assay.

Results: The tumor volumes of luteinizing hormone-releasing hormone receptor-positive HEC-1B and NIH:OVCAR-3 cancers were reduced significantly (P <.001) 1 week after treatment with AN-152 at 700 nmol/20 g or at 300 nmol/20 g. No toxic side effects were observed. Treatment with doxorubicin arrested tumor growth but did not reduce tumor volume. Doxorubicin at 700 nmol/20 g caused a high mortality rate and at 300 nmol/20 g (8.7 mg/kg) caused a loss of body weight, but no deaths occurred. The growth of luteinizing hormone-releasing hormone receptor-negative SK-OV-3 cancers was not affected by AN-152. Normal human nonreproductive tissues, hematopoietic stem cells, and vaginal tissue did not express luteinizing hormone-releasing hormone receptors, but luteinizing hormone-releasing hormone receptors were found in the ovary, fallopian tube, cervix, endometrium, and myometrium.

Conclusion: Targeted chemotherapeutic luteinizing hormone-releasing hormone analog AN-152 is more effective and less toxic than cytotoxic radical doxorubicin on luteinizing hormone-releasing hormone receptor-positive tumors. AN-152 could be considered for targeted chemotherapy in patients with ovarian or endometrial cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Binding Sites
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / therapeutic use*
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology
  • Female
  • Gonadotropin-Releasing Hormone / analogs & derivatives*
  • Gonadotropin-Releasing Hormone / metabolism
  • Gonadotropin-Releasing Hormone / therapeutic use*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • RNA, Messenger / analysis
  • Receptors, LHRH / drug effects
  • Receptors, LHRH / genetics
  • Receptors, LHRH / metabolism
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


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