INACTIVATION OF P53 IN A HUMAN OVARIAN-CANCER CELL-LINE INCREASES THESENSITIVITY TO PACLITAXEL BY INDUCING G2 M ARREST AND APOPTOSIS/

Paclitaxel-induced cytotoxicity, cell cycle perdurbation, and apoptosi s were determined in a human ovarian cancer cell Line expressing wt p5 3 (A2780) and in a subclone (A2780/E6) obtained upon transfection with the product of the E6 gene of the human papilloma virus HPV16. The in activation of wt p53 in A2780/E6 was verified by measuring the inabili ty of the clone to induce p53 and p21 expression after paclitaxel trea tment. The p53-negative clone (A2780/E6) was approximately 50-fold mor e sensitive to paclitaxel than wt p53-expressing A2780 cells. This inc reased sensitivity was related to the ability of paclitaxel to induce a strong arrest of cells in the G2/M phase of the cell cycle in A2780/ E6 but not in A2780 cells. This different cell cycle arrest was accomp anied by increased frequency of paclitaxel-induced p53-independent apo ptosis, Initial studies on proteases activation tend to exclude a dire ct role of ICE: and CPP32 in the induction of apoptosis in these cells and show a paclitaxel-dependent increase in FLICE levels, whose biolo gical relevance is however at present not defined. (C) 1998 Academic P ress.