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.

J. M. Arencibia, Andrew V Schally, M. Krupa, A. M. Bajo, A. Nagy, K. Szepeshazi, A. Plonowski

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)571-577
Number of pages7
JournalInternational Journal of Oncology
Volume19
Issue number3
StatePublished - Sep 1 2001
Externally publishedYes

Fingerprint

LHRH Receptors
Nude Mice
Gonadotropin-Releasing Hormone
Ovarian Neoplasms
Doxorubicin
Epidermal Growth Factor Receptor
Vascular Endothelial Growth Factor A
Messenger RNA
Growth
Oncogenes
Neoplasms
Intercellular Signaling Peptides and Proteins
Body Weight
Carcinoma
Drug Therapy
Polymerase Chain Reaction
Injections
lysine(6)-doxorubicin LHRH
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Arencibia, J. M.; Schally, Andrew V; Krupa, M.; Bajo, A. M.; Nagy, A.; Szepeshazi, K.; Plonowski, A.

In: International Journal of Oncology, Vol. 19, No. 3, 01.09.2001, p. 571-577.

Research output: Contribution to journalArticle

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abstract = "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.",
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