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1st World Conference on Physico-Chemical Methods in Drug Discovery and Development
Tumor targeting with gonadotropin-releasing hormone derivatives
Marilena Manea1,2, Ildikó Szabó3, Erika Orbán3, Miguel Tejeda4, Bence Kapuvári4, Žarko
Kulić1,5, Peter Öhlschläger6, Wilfried Reichardt7, Dezső Gaál4 and Gábor Mező3
1
Laboratory of Analytical Chemistry and Biopolymer Structure Analysis, Department of
Chemistry, University of Konstanz, Konstanz, Germany; 2Zukunftskolleg, University of
Konstanz, Konstanz, Germany; 3Research Group of Peptide Chemistry, Hungarian
Academy of Sciences, Eötvös L. University, Budapest, Hungary; 4National Institute of
Oncology, Budapest, Hungary; 5NMR Spectroscopy, Department of Chemistry, University
of Konstanz, Konstanz, Germany; 6Laboratory of Immunology, Department of Biology,
University of Konstanz, Konstanz, Germany; 7Department of Diagnostic
Radiology/Medical Physics, University Hospital Freiburg, Freiburg, Germany
Targeted cancer chemotherapy has been developed in order to overcome the drawbacks
associated with the application of free anticancer drugs (e.g. lack of selectivity, toxic side
effects, multidrug resistance of cancer cells). The attachment of anticancer drugs to a
targeting moiety that recognizes tumor-specific or overexpressed receptors on cancer cells
might provide efficient chemotherapeutic agents with minimal systemic toxicity. It was
found that receptors for peptide hormones, such as gonadotropin-releasing hormone
(GnRH), are overexpressed on cancer cells. Consequently, GnRH and its derivatives can be
used as targeting moieties to deliver cytotoxic agents directly to tumor cells, thereby
increasing the concentration of the drugs in the tumor tissue and sparing normal cells from
unnecessary exposure. One of the most promising natural GnRH analogs isolated from sea
lamprey is GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2) which specifically
binds to GnRH receptors on cancer cells and has lower hormonal effect in mammals than
the human GnRH. Daunorubicin (Dau) and doxorubicin (Dox), anthracycline antibiotics
widely used in cancer chemotherapy, were attached to the ε-amino group of 8Lys of
monomeric GnRH-III via ester, hydrazone, oxime or amide bonds either directly or by
insertion of a GFLG tetrapeptide spacer. The drug release from the bioconjugates was
determined in the presence of Cathepsin B, chymotrypsin, as well as in human, rat and
mouse sera and in rat liver lysosomal homogenates by liquid chromatography in
combination with mass spectrometry. The in vitro long term antitumor effect of the
compounds was studied on various cancer cell lines such as MCF-7 human breast, C26
murine colon, HT-29 human colon cancer cell lines. The in vivo antitumor activity of free
daunorubicin, oxime bond linked GnRH-III(Dau=Aoa-GFLG) conjugate, GnRH-III or
GnRH-III(GFLG) hormone analog was determined on C26 colon cancer bearing mice and
on TRAMP model (transgenic adenocarcinoma of the mouse prostate). The conjugate had
lower toxic effect than the free daunorubicin and its administration resulted in ~ 50% tumor
growth inhibition and longer survival time of C26 colon cancer bearing mice and TRAMP
mice.
Acknowledgement
This work was supported by grants from the Hungarian National Science Fund (OTKA
T049814, NK 77485), the Ministry of Health (ETT 202/2006), GVOP-3.2.1.-2004-040005/3 and Zukunftskolleg and AFF (Project 01/09), University of Konstanz.