Ekotoksičnost izbranih tirozin kinaznih inhibitorjev ocenjena z eksperimentalnim modelom zarodkov rib cebric

Žalec, Nika (author), Eleršek, Tina (mentor)

Vse pogosteje uporabljeni farmacevtiki so zdravila za zdravljenje raka. Med njimi so pravi terapevtski preboj doživeli tirozin kinazni inhibitorji (TKI). S svojim delovanjem neposredno inhibirajo določene tirozin kinaze, ki so prekomerno izražene v rakavih celicah, in tako preprečujejo širjenje bolezni. Ker je rak v današnjem času vse pogostejša bolezen, poraba teh zdravil vsako leto narašča, s tem pa narašča njihova prisotnost v okolju. Zaradi posebnega mehanizma delovanja TKI predstavljajo tveganje za ne-ciljne organizme v okolju. Namen naše raziskave je bil preučiti ekotoksičnost TKI na eksperimentalnem modelu z zarodki rib cebric (Danio rerio). Posamezne zarodke smo na ploščah izpostavili posameznim TKI v določeni koncentraciji – imatinibu, erlotinibu in dasatinibu. Določanje letalnih, sub-letalnih in teratogenih učinkov je potekalo pod določenimi pogoji standardnega postopka OECD 236. Na podlagi učinkov smo izračunali ekotoksikološke parametre, potrebne za oceno tveganja za okolje. Ugotovili smo, da po 96-urni izpostavitvi imatinib povzroča letalne učinke od 238,9 mg/l naprej, erlotinib do 15,6 mg/l ne povzroča nobenih učinkov, dasatinib pa povzroča tako letalne kot sub-letalne/teratogene učinke – letalne od 61,8 mg/l naprej, sub-letalne/teratogene od 0,6 mg/l naprej. Dasatinib povzroča predvsem nastajanje krvnih strdkov, ki se pri imatinibu in erlotinibu redko pojavljajo. Vsi trije TKI znižujejo odstotek izvaljenih zarodkov, kar negativno vpliva na viabilnost populacij v naravi.

• Language: Slovenian
• Keywords: cebrice, tirozin kinazni inhibitorji, ekotoksičnost, letalni učinki
• Work type: Master's thesis/paper
• Organization: BF - Biotechnical Faculty
• Year: 2019
• PID: 20.500.12556/RUL-113341
• COBISS.SI-ID: 5266767
• Publication date in RUL: 21.12.2019

Secondary language

• Language: English
• Title: Ecotoxity of selected tyrosine kinase inhibitors assessed with zebrafish (Danio rerio) embryo model

Abstract

Pharmaceutical drugs for curing cancer are being more extensively used on a day to day basis. Tyrosine kinase inhibitors (TKIs) are the ones that have undergone the real therapeutical breakthrough as they directly inhibit certain tyrosine kinases which are over-expressed in the cancer cells and therefore prevent the disease from spreading. As cancer is becoming a common disease in the modern world, so is the use of the drugs against it and therefore their presence in the environment increases. The TKIs present a risk for the non-target organisms in the water environment due to a special functioning mechanism. The purpose of this research was to study the ecotoxicity of the TKIs on an experimental model of zebrafish (Danio rerio) embryos. Certain embryos were exposed to different concentrations of the chosen TKIs – imatinib, erlotinib and dasatinib. Assessment of lethal, sub-lethal and teratogenic effects was done under defined conditions of a standard procedure OECD 236. Based on the effects, ecotoxicological parameters were calculated. Ecotoxicological parameters are needed to assess the risk for the environment. It was discovered that after a 96-hour exposure imatinib causes lethal effects from 238.9 mg/l onwards, erlotinib does not cause any effects up to 15.6 mg/l and dasatinib causes lethal and sub-lethal/teratogenic effects, lethal from 61.8 mg/l and sub-lethal/teratogenic from 0.6 mg/l. Dasatinib causes large numbers of thrombi, that rarely occure at imatinib and erlotinib. All three TKIs lower the hatching rate of embryos, which can negatively affects the viability of populations in the wild.

• Keywords: zebrafish, tyrosine kinase inhibitors, ecotoxity, lethal effects