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  • Title: 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.
    Author: Arencibia JM, Schally AV, Krupa M, Bajo AM, Nagy A, Szepeshazi K, Plonowski A.
    Journal: Int J Oncol; 2001 Sep; 19(3):571-7. PubMed ID: 11494038.
    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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