Journal
JOURNAL OF PEPTIDE SCIENCE
Volume 21, Issue 5, Pages 426-435Publisher
WILEY
DOI: 10.1002/psc.2775
Keywords
targeted tumor therapy; gonadotropin-releasing hormone; targeting unit; receptor binding affinity; long-term cytotoxic effect; apoptotic effect
Funding
- Hungarian National Science Fund [OTKA PD 104012, K 104045, K 81596]
- European Union
- European Social Fund
- [TAMOP 4.2.2.A-11/1/KONV-2012-0025]
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Hormone based drug targeting is a promising tool for selective tumor therapy. In this study, synthesis and systematic comparative biological evaluation of novel drug containing analogs of gonadotropin-releasing hormone GnRH-I and GnRH-II is reported demonstrating their suitability for tumor targeting. The cytotoxic conjugates were prepared by the attachment of the chemotherapeutical agent daunorubicin (Dau) to GnRH analogs directly or through an enzyme-labile spacer with oxime linkage. All conjugates were found to be proteolytically stable under circumstances applied in biological assays. Both GnRH-I and GnRH-II were able to bind similarly to high-affinity GnRH-I receptors on human pituitary and human prostate cancer cells. The in vitro long-term cytotoxic effect of the conjugates was comparable with that of the free drug in human breast and colon cancer cell lines. Furthermore, a concentration-dependent cellular uptake profile was observed. The in vitro apoptotic effect of the compounds was evaluated by flow cytometry analysis using annexin-V. Our results show that both the GnRH-I and the GnRH-II based analogs might be applied for targeted tumor therapy. Copyright (c) 2015 European Peptide Society and John Wiley & Sons, Ltd.
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