1Department of Gynecology, Universitätsklinik Freiburg, Germany 2 Lilly Deutschland GmbH, Bad Homburg, Germany
The development of tumoral cell resistence aginst commonly used cytostatika is one of the most relevant problems in ovarian cancer therapy. For this reason it is important to develop and research new and more effective antitumoral drugs. Gemcitabine (2´,2-Difluorodeoxycytidin/dFdC) is a new nucleoside analogue cytostatika, which is at present clinically tested in the therapy against solid tumors. The aim of this work is to investigate in an in vitro approach the influence of Gemcitabine concentrations on the cell cycle, proliferation and apoptosis on ovarian cancer cell lines. We studied the ovarian adenocarcinoma cell line HEY, in order to determine the optimal dosis needed to achieve a maximal effect of cell death and to prevent resistence. HEY was treated with Gemcitabine in a dose and time dependent manner. Cell cyclus analysis were performed with a FacScan analyzer (Beckton & Dickinson), and related proteins were analyzed by Western-blotting. At low concentrations (0,003 - 0,012 µg/ml) cell cycle arrest in S phase followed by apoptosis at 48 hs post-treatment was observed. P53 accumulated up to 8 fold in the first 24 hs. Concomitantly, PCNA was down regulated whereas Bax protein level was increased slowly within 8 hs. At high dosis (0,3 - 3 µg/ml) cells arrested in G1 phase and underwent apoptosis. P53 accumulated only up to 2,5 fold, PCNA was not significatively affected, and Bax levels decreased at 16 hs. We suggest that down regulation of p53 through Gemcitabine could contribute to an anti-apoptotic effect or to the development of resistence in this cell line in a dose and time dependent manner.
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