Vysoká efektivita adamantylaminových platinových komplexů při překonávání rezistence k cisplatině a potlačení proliferace ovariálních nádorových buněk in vitro

Ing. Viktor Horváth, Ph.D.

Doctoral thesis

High effectiveness of platinum complexes with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro

Abstract:

Currently, platinum-based drugs (cisplatin and carboplatin) remain still the most important conventional cytotoxic agents used in 1st-line combination chemotherapy protocols for treating ovarian cancer patients with overall response rate exceeding 80 % when integrated with cytoreductive surgery. However, despite widespread clinical use and strong antitumor activity of cisplatin, its effects are often decreased due to intrinsic or acquired resistance. The resistance of tumor cells to cisplatin remains a major cause of treatment failure in cancer patients. Moreover, cisplatin therapy can lead to a number of side effects such as nephrotoxicity, neurotoxicity, and emetogenesis. The toxicity of cisplatin limits the dose that can be given to patients. These facts together with the aim to find platinum-based derivatives with higher antitumor activity, displaying more tolerable toxicological profile and overcoming resistance in many tumor types have led many investigators to attempt the synthesis and characterization of new platinum agents. Therefore, we aimed to study in more detail the in vitro cytotoxicity, overcoming of resistance, cell cycle perturbations, and the type of cell death induced by the novel platinum (Pt) derivatives with adamantylamine, LA-12 and its counterpart with lower oxidation state LA-9, and compared these effects to those of well established anticancer drug cisplatin, in ovarian cancer cell lines with different sensitivity to cisplatin (A2780 - parent, cisplatin sensitive; A2780cis - with acquired cisplatin resistance; SK-OV-3 with intrinsic resistance to cisplatin). Interestingly, the novel Pt(IV) complex with adamantylamine - LA-12 - was characterized by significantly higher cytotoxicity than cisplatin in A2780 (cisplatin sensitive), A2780cis (with acquired cisplatin resistance) and SK-OV-3 (with intrinsic cisplatin resistance) ovarian cancer cell lines and overcame both the acquired and the intrinsic resistance to cisplatin. In summary, our results may contribute to better understanding of unknown molecular mechanisms of action, the effect on basic cytokinetic parameters and/or overcoming of resistance caused by the novel platinum derivatives with adamantylamine in comparison to the effects caused by well established anticancer drug - cisplatin. Moreover, this study concerning the evaluation of the anticancer effects of the novel platinum derivatives may reveal us the knowledge important for developing of new platinum-based compounds and its utilization in the (ovarian) cancer treatment management.

Keywords

karcinom ovarií, cisplatina, adamantylamin, LA-12, LA-9, cytotoxicita, modulace buněčného cyklu, apoptóza, rezistence, ovarian cancer, cisplatin, adamantylamine, cytotoxicity, cell cycle modulation, apoptosis, resistance

Language used: English

Date on which the thesis was submitted / produced: 22. 6. 2006

Thesis defence

• Date of defence: 22. 6. 2006
• Supervisor: doc. RNDr. Peter Fedoročko, CSc.

Masaryk University

Faculty of Science

Doctoral programme / field:
Biology / Physiology and Evolutionary Biology of Animals