Nová protinádorová léčiva zasahující do buněčného cyklu

Mgr. Jiří ŘEHULKA

Doctoral thesis

Abstract:

Poruchy v regulaci bun..neho cyklu spolu s nadm.rnou aktivaci proliferace jsou hlavnimi p.i.inami karcinogeneze. Teoreticky uvod prace p.ibli.uje regula.ni mechanismy bun..neho cyklu i nej.ast.ji pou.ivana klinicka a experimentalni cytostatika. P.edm.tem teto diserta.ni prace byla charakterizace protinadorove aktivity nizkomolekularnich latek pelorusidu A a semisyntetickych derivat. triterpen.. Vysledky teto prace prokazuji, .e aktivita pelorusidu A neni na rozdil od paklitaxelu negativn. ovlivn.na hypoxii v podminkach in vitro. P.esto.e pelorusid A stejn. jako paklitaxel stabilizuje mikrotubuly, jejich odli.ne ?Ŕ-tubulin vazebne misto je z.ejm. p.i.inou rozdilne citlivosti v..i hypoxii indukovanym zm.nam v bu.kach kolorektalniho karcinomu. V dal.i .asti prace byla studovana protinadorova aktivita novych triterpen. a jejich modula.ni vliv na bun..ny cyklus linie T-lymfoblasticke leukemie. Cytotoxicita derivat. byla zavisla na p.itomnosti substituentu v poloze 2 a korelovala s elektronegativitou substituentu. Neju.in.j.i derivaty kyseliny dihydrobetulinove, oleanonove a methyl betulonatu indukovaly akumulaci bun.k v S a G2/M fazi bun..neho cyklu.

Abstract:

The cell cycle is a complex sequence of events that directs cell growth and division. Importantly, the cell cycle regulation is frequently impaired in human cancer cells. The carcinogenesis relies on the multistep accumulation of genetic alterations that results in deregulated tumor growth. The majority of current chemotherapeutics activate cell cycle checkpoints such as DNA damage checkpoint or spindle assembly checkpoint. Although new targeting strategies are being developed, they still require combination with conventional drugs. The theoretical part of the thesis introduces the regulation of cell cycle and summarizes the most important anticancer agents currently used in clinics as well as novel cell cycle inhibitors. Experimental part evaluates anticancer activity of non-taxoid microtubule stabilizing drug peloruside A and novel semisynthetic triterpene derivatives. The data show, that in contrast to paclitaxel, peloruside A maintains the activity in hypoxia pre-exposured human colorectal carcinoma cells. Study of novel triterpene analogues with unknown mode of action revealed their cell cycle modulatory properties. The most active derivatives of dihydrobetulinic acid, oleanonic acid and methyl betulonate induced cell cycle arrest in S or G2/M phase. The study clearly demonstrated that modification of triterpenes with electronegative substituents such as fluorine or thiocyanate moiety at carbon 2 significantly improve in vitro anticancer activity.

Keywords

buněčný cyklus, apoptóza, mikrotubule

Language used: Czech

Date on which the thesis was submitted / produced: 27. 6. 2017

Thesis defence

• Date of defence: 30. 6. 2017

PALACKÝ UNIVERSITY OLOMOUC

Faculty of Medicine and Dentistry

Doctoral programme / field:
Paediatrics / Pediatrics