dc.contributor.advisor | Ninković, Srđan | |
dc.contributor.other | Zarić, Milan | |
dc.contributor.other | Petronijević, Nataša | |
dc.contributor.other | Živković, Marija | |
dc.contributor.other | Spasić, Marko | |
dc.creator | Marković, Nenad | |
dc.date.accessioned | 2020-10-24T12:35:02Z | |
dc.date.available | 2020-10-24T12:35:02Z | |
dc.date.issued | 2020-07-27 | |
dc.identifier.uri | http://eteze.kg.ac.rs/application/showtheses?thesesId=7548 | |
dc.identifier.uri | https://fedorakg.kg.ac.rs/fedora/get/o:1261/bdef:Content/download | |
dc.identifier.uri | https://nardus.mpn.gov.rs/handle/123456789/17543 | |
dc.description | 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. | sr |
dc.description | 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 was126
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. | en |
dc.format | application/pdf | |
dc.language | sr | |
dc.publisher | Универзитет у Крагујевцу, Факултет медицинских наука | sr |
dc.rights | openAccess | en |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | Универзитет у Крагујевцу | sr |
dc.subject | 4T1 | sr |
dc.subject | 4T1 | en |
dc.subject | MDA-MB-231 | sr |
dc.subject | karcinom dojke | sr |
dc.subject | dinuklearni kompleksi platine(II) | sr |
dc.subject | infracrvena i NMR spektroskopija | sr |
dc.subject | oksaliplatina | sr |
dc.subject | cisplatina | sr |
dc.subject | MDA-MB-231 | en |
dc.subject | breast cancer | en |
dc.subject | platinum (II) dinuclear complexes | en |
dc.subject | infrared and NMR spectroscopy | en |
dc.subject | oxaliplatin | en |
dc.subject | cisplatin | en |
dc.title | Citotoksičnost novosintetisanih dinuklearnih kompleksa platine(II) na ćelije karcinoma dojke in vitro | sr |
dc.type | doctoralThesis | en |
dc.rights.license | BY-NC-ND | |
dcterms.abstract | Нинковић, Срђан; Зарић, Милан; Спасић, Марко; Живковић, Марија; Петронијевић, Наташа; Марковић, Ненад; Цитотоксичност новосинтетисаних динуклеарних комплекса платине(ИИ) на ћелије карцинома дојке ин витро; Цитотоксичност новосинтетисаних динуклеарних комплекса платине(ИИ) на ћелије карцинома дојке ин витро; | |
dc.identifier.fulltext | https://nardus.mpn.gov.rs/bitstream/id/66167/Izvestaj_Nenad_Markovic_Medicina.pdf | |
dc.identifier.fulltext | https://nardus.mpn.gov.rs/bitstream/id/66166/Disertacija.pdf | |
dc.identifier.rcub | https://hdl.handle.net/21.15107/rcub_nardus_17543 | |