Szabó Ildikó, Bősze Szilvia, Orbán Erika, Sipos Éva, Halmos Gábor, Kovács Magdolna, Mező Gábor
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, 1117, Budapest, Hungary.
J Pept Sci. 2015 May;21(5):426-35. doi: 10.1002/psc.2775. Epub 2015 Apr 24.
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.
基于激素的药物靶向是一种有前景的选择性肿瘤治疗工具。在本研究中，报告了新型含促性腺激素释放激素GnRH-I和GnRH-II类似物的药物的合成及系统的比较生物学评价，证明了它们适用于肿瘤靶向。细胞毒性缀合物是通过将化疗药物柔红霉素（Dau）直接或通过具有肟键的酶不稳定间隔物连接到GnRH类似物上制备的。在生物测定中应用的条件下，所有缀合物都被发现具有蛋白水解稳定性。GnRH-I和GnRH-II都能够与人垂体和人前列腺癌细胞上的高亲和力GnRH-I受体类似地结合。缀合物在人乳腺癌和结肠癌细胞系中的体外长期细胞毒性作用与游离药物相当。此外，观察到了浓度依赖性的细胞摄取情况。使用膜联蛋白-V通过流式细胞术分析评估了化合物的体外凋亡作用。我们的结果表明，基于GnRH-I和GnRH-II的类似物都可能用于靶向肿瘤治疗。
