Akademik Veri Yönetim Sistemi
Tezin Türü: Doktora
Tezin Yürütüldüğü Kurum: Bursa Uludağ Üniversitesi, FEN-EDEBİYAT FAKÜLTESİ, BİYOLOJİ, Türkiye
Tezin Onay Tarihi: 2010
Tezin Dili: Türkçe
Öğrenci: FERDA ARI
Danışman: Egemen Dere
Özet:
Decitabine as a demethylating agent may act synergistically with standard chemotherapy regimens to restore apoptosis by upregulation of epigenetically silenced genes. In this study, we investigated whether or not the combination of classical FEC treatment (5-FU+Epirubicine+4-Hydroxyclophosphamide) with decitabine might be a novel therapy option in breast cancer.The effect of decitabine and its combination with FEC has been tested on estrogen receptor negative (MDA-MB-231) and estrogen receptor positive (MCF-7) breast cancer cell lines. The changes in the methylation status of uPA, PAI-1 (metastasis promoter), DAPK, TMS1 (apoptosis-inducer) MGMT (DNA repair) genes and LINE-1 (global methylation marker) have been analyzed by methylation specific realtime PCR (methylight) after the application of decitabine, FEC and their combination treatment. Anti-growth effects of treatments were assayed by the MTT assay and the ATP assay; induction of apoptosis by the M30 antigen assay.It is shown that decitabine had anti-growth effect only on MCF-7 cells by induction of apoptosis but had no effect on MDA-MB-231 cells. However, LINE-1 methylation status significantly decreased after combination treatment (%100 TDC FEC+10µM decitabine) (p<0.05) which show that whole genom methylation decreased in both cell lines. The methylation ratio of DAPK promoter was significantly decreased after decitabine (10µM) and combination regimens in both cell line. In MDA-MB-231 cells, methylation of the TMS1 gene promoter was significantly reduced by combination treatment (p<0.05). Although these results, it?s found that apoptosis only induced in MCF-7 cell lines by M30 antigen test. In addition methylation of the uPA and PAI-1 promoter was significantly reduced by treatment with decitabine or the combination treatment in MCF-7 (p<0.05). This shows that the ability of metastasis may change in these cells.In conclusion, combination of standard chemotherapy with the combination of demethylating agents may influence therapy outcome by upregulation of apoptosis relevant genes in breast cancer therapy. But reactivation of metastasis genes shows that these therapies have to be used carefully according to tumor types.