Targeting of doxorubicin to ES-2 human ovarian cancers in nude mice by linking to an analog of luteinizing hormone-releasing hormone improves its effectiveness

Int J Oncol. 2001 Sep;19(3):571-7. doi: 10.3892/ijo.19.3.571.


Receptors for luteinizing hormone-releasing hormone (LHRH), expressed by ovarian cancers, can be used for targeting chemotherapeutic compounds more selectively to these tumors. We investigated the effects of cytotoxic LHRH analog AN-152, consisting of doxorubicin (DOX)-14-O-hemiglutarate linked to the epsilon-amino group of [D-Lys6]LHRH, on the growth of LHRH receptor-positive ES-2 human ovarian cancer line xenografted into nude mice. A single injection of AN-152, at a dose of 345 nmol/20 g body weight, caused a 34.5% reduction (P<0.05) in tumor growth after 28 days, while its cytotoxic moiety DOX was inactive at the same dose. Since the overexpression of certain growth factors and/or their receptors, such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and HER-2/neu, as well as various oncogenes like c-fos and c-jun, is associated with unfavorable prognosis and contributes to progressive growth of ovarian carcinomas, their mRNA levels were analyzed by RT-PCR. Treatment with AN-152 significantly (P<0.05) reduced the expression of EGFR, VEGF, c-fos and c-jun, to 49%, 48%, 55% and 58% respectively, compared to controls. HER-2/neu mRNA expression was also decreased to non-detectable levels. Conversely, DOX decreased non-significantly the expression levels for EGFR by 32%, VEGF 35%, both c-fos and c-jun approximately 20% and HER-2/neu by only 15%. In conclusion, cytotoxic LHRH analog AN-152 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • DNA Primers / chemistry
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / therapeutic use*
  • Endothelial Growth Factors / genetics
  • ErbB Receptors / genetics
  • Female
  • Gonadotropin-Releasing Hormone / analogs & derivatives
  • Gonadotropin-Releasing Hormone / metabolism*
  • Gonadotropin-Releasing Hormone / therapeutic use*
  • Humans
  • Lymphokines / genetics
  • Mice
  • Mice, Nude
  • Middle Aged
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antineoplastic Agents
  • DNA Primers
  • Endothelial Growth Factors
  • Lymphokines
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • LHRH, lysine(6)-doxorubicin
  • Gonadotropin-Releasing Hormone
  • Doxorubicin
  • ErbB Receptors
  • Receptor, ErbB-2