Naslov (srp)

Цитотоксичност новосинтетисаних динуклеарних комплекса платине(II) на ћелије карцинома дојке in vitro

Autor

Marković, Nenad, 1984-, 56511497

Doprinosi

Ninković, Srđan, 1963-, 7111783
Zarić, Milan, 1982-, 24932967
Petronijević, Nataša, 1963-, 12636007
Živković, Marija, 1979-, 13619047
Spasić, Marko, 1980-, 9302119

Opis (eng)

Introduction: The routine use of platinum preparations discovered so far in oncology has its drawbacks and limitations, which is their toxic effect, limited solubility and the appearance of resistance after prolonged administration. To overcome the disadvantages of platinum derivatives, and in particular toxicity, a number of platinum (II) complexes such as carboplatin, oxaliplatin, nedaplatin, lobaplatin, and heptaplatin have been synthesized. A further shift was made by the synthesis of complexes containing two or more platinum ions linked by bridge ligands, the so-called polynuclear platinum complexes but they also had some limitations in their application. Material and Methods: This study was conducted by type of experimental study on material of human and animal origin in vitro. We synthesized the corresponding platinum (II) complexes, [{Pt (en) Cl} 2 (µ-1,7-phen)} (ClO4) 2 and [{Pt (en) Cl} 2 (µ-4,7-phen )} (ClO4) 2, where the 1,7-phen bridge ligand is 1,7-phenanthroline and 4,7-phenanthroline, respectively. We characterized the same complexes by the methods of elemental microanalysis and spectroscopy. The in vitro antitumor effect of the synthesized complexes was demonstrated by MTT assay,analysis of Annexin V and propidium iodide stained cells, analysis of molecules involved in apoptosis (Bax, Bcl-2, caspase-3) and cell cycle analysis. Results: In our study, after characterizing the two K1 and K2 complexes, we demonstrated that both complexes, especially K1, have a more pronounced cytotoxic effect on breast cancer cell lines in vitro of both human and animal origin. On the other hand, our results show that the effect of these complexes on healthy MRC-5 fibroblasts is less cytotoxic than conventional platinumderived chemotherapeutics. This fact might suggest that newly synthesized drugs based on dinuclear platinum complexes would be less toxic and therefore safer for routine use. Conclusion: The dinuclear platinum (II) complexes used in this thesis are water-soluble and oxaliplatin-like in structure for the treatment of breast cancer patients, and in particular for aggressive forms of this disease. We have shown that the newly synthesized dinuclear platinum (II) complexes exhibit a more pronounced cytotoxic effect on breast cancer cells in vitro compared with cisplatin and oxaliplatin. Through this experimental work, we have identified novel dinuclear platinum (II) complexes that could be used in future studies in the field of platinum coordination with ligands of pharmacological importance.

Opis (srp)

Uvod: Rutinska primena do sada otkrivenih preparata platine u onkologiji ima svoje nedostatke i ograničenja, a to je njihovo toksično dejstvo, ograničena rastvorljivost i pojava rezistencije nakon duže primene. Da bi se prevazišli nedostaci derivata platine, a posebno toksičnost, sintetisan je veliki broj kompleksa platine(II) kao što su karboplatina, oksaliplatina, nedaplatina, lobaplatina i heptaplatina (4). Još veći pomak je napravljen sintezom kompleksa koji sadrže dva ili više jona platine povezanih mostnim ligandima, tzv. polinuklearni kompleksi platine ali i oni su imali izvesna ograničenja u primeni. Materijal i metode: Ova studija je sprovedena po tipu eksperimentalne studije na materijalu humanog i animalnog porekla in vitro. Sintetisali smo odgovarajuće platina(II) komplekse, [{Pt(en)Cl}2(µ-1,7-phen)}(ClO4)2 i [{Pt(en)Cl}2(µ-4,7-phen)}(ClO4)2, gde je 1,7-phen mostni ligand 1,7-fenantrolin, odnosno 4,7-fenantrolin. Iste komplekse smo metadama elementarne mikroanalize i spektroskopije okarakterisali. Antitumorski efekat sintetisanih kompleksa in vitro smo dokazali MTT testom, analizom ćelija obojenih Annexin-om V i propidijum jodidom, analizom molekula uključenih u proces apoptoze (Bax, Bcl-2, kaspaza-3) i analizom ćelijskog ciklusa. Rezultati: U našem istraživanju nakon šo smo okarakterisali dva kompleksa K1 i K2 dokazali smo da oba kompleksa, naročito K1 imaju izraženiji citotoksični efekat na ćelijske linije karcinoma dojke in vitro kako humanog tako i animalnog porekla. Sa druge strane naši rezultati pokazuju da efekat ovih komplesa na zdrave fibroblaste iz linije MRC-5 je manje cititoksičan u odnosu na konvencionalne hemioterapeutike iz grupe derivata platine. Ova činjenica bi mogla biti pretpostavka da bi novosintetisani lekovi na bazi dinuklearnih kompleksa platine bili manje toksični a samim tim i bezbedniji za rutinsku primenu. Zaključak: Dinuklearni kompleksi platine(II) koji su upotrebljeni u ovoj tezi su rastvorni u vodi i po strukturi slični oksaliplatini koja se koristi za lečenje obolelih od karcinoma dojke, a naročito agresivnih oblika ove bolesti. Pokazali smo da novosintetisani dinuklearni kompleksi platine(II) pokazuju izraženiji citotoksični efekat na ćelije karcinoma dojke in vitro u poređenju sa cisplatinom i oksaliplatinom. Ovim eksperimentalnim radom ukazali smo na nove dinuklearne komplekse platine(II)124 koji bi se mogli koristiti u narednim istraživanjima u oblasti koordinovanja platine sa ligandima od farmakološkog značaja.

Jezik

srpski

Datum

2020

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 2.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 2.0 Austria License.

CC BY-NC-ND 2.0 AT

http://creativecommons.org/licenses/by-nc-nd/2.0/at/