Akademik Veri Yönetim Sistemi
Tezin Türü: Doktora
Tezin Yürütüldüğü Kurum: Orta Doğu Teknik Üniversitesi, Fen Edebiyat Fakültesi, Biyolojik Bilimler Bölümü, Türkiye
Tezin Onay Tarihi: 2014
Öğrenci: DERYA DİLEK KANÇAĞI
Danışman: NÜLÜFER TÜLÜN GÜRAY
Özet:Metabolic changes observed in prostate cancer are very important for both the course of the event and therapeutic way to be decided. One of the effective chemotherapeutic agent showing antitumour activity against prostate cancer is Docetaxel. The metabolism of this drug is important in term of its effectiveness. In this study we determine the effect of CYP1A1, CYP3A4 and GSTP1 enzyme inhibitors on the efficacy of the docetaxel. For this purpose, the gene expressions and activities of these enzymes were analyzed in PC3 (androgen-independent PC cell lines) and PNT1A (immortalized prostatic cell lines) cells by using real-time PCR and activity assays. Alpha-naphthoflavone, ketaconozole and quercetin were used as the inhibitors of CYP1A1, CYP3A4 and GSTP, respectively. In order to investigate the potential of these inhibitors in docetaxel metabolism, PC3 and PNT1A cells were treated with inhibitors in combination with docetaxel and the cell viability and cell death (apoptosis/necrosis) was analyzed by using WST-1 and Annexin V assays, respectively. According to our results, the concentration which gives 70% and 60% cell viability after 24 and 48 hours applications were found as 4 µM for docetaxel, 1000 nM for alpha-naphthoflavone, 56.5 µM for ketoconazole and 300 µM for quercetin. IC50 values were calculated as 15.1 µM for alpha-naphthoflavone, 118.7 µM for ketoconazole and 692 µM for quercetin from the activity assays. Docetaxel application alone and in combination with the inhibitors showed differences in both mRNA levels and cell viability status in treated/untreated PC3 and PNT1A cells at predetermined concentrations. In conclusion, our results showed that, the application of docetaxel with enzyme specific inhibitors is more effective by increasing the effects of docetaxel in PC3 cells. Further studies about the metabolism of drugs will help for the development of a therapy that would increase the efficacy of the drugs which might provide a better chance for the patience survival.