RADIATION AND TAXOL EFFECTS ON SYNCHRONIZED HUMAN CERVICAL-CARCINOMA CELLS

Purpose: To evaluate the effectiveness of the plant derived chemothera peutic agent taxol alone and in combination with ionizing radiation on synchronous and asynchronous human cervical carcinoma cells and to de fine the mechanistic basis for this cytotoxic response. Methods and Ma terials: Asynchronous and synchronous cells (obtained by modified mito tic shake-off) derived from carcinomas of the human uterine cervix wer e treated with a range of concentrations of taxol (0, 1.0, 2.5, 5.0, 1 0.0 and 20.0 nM) for either 8, 24 or 48 h. Synchronized cell cycling w as evaluated by counting mitotic indices and by uptake of bromodeoxyur idine (BrdUrd). Cells were irradiated (Cs-137 gamma rays at 1.12 Gy/mi n) alone and after taxol treatment and plating efficiencies and radios ensitivity determined. Results: Taxol treatment resulted in a dose tim e dependent loss of colony forming ability with 10 nM for 24 h produci ng about 10% cell survival. Irradiating taxol treated cells resulted i n a strictly additive response in contrast to previous supra-additive results with astrocytoma and melanoma cells. Mitotically synchronized cells rapidly moved into G(1) phase with a second mitotic peak at 28 h (total cycle time). Taxol treatment resulted in a continued accumulat ion of mitoses, and a failure and/or delay of entry of a fraction of c ells into S phase after a G(1) phase of at least 10 h, That is, taxol effects cell cycling at a stage other than G(2)/M. Irradiating (3 Gy) synchronized cells showed a 10-fold variation in sensitivity, with mit osis as the most sensitive phase with taxol alone resulting in some cy totoxicity and combined effects additive or less than additive. Conclu sion: Taxol effects these cervical carcinoma cells at other stages of the cell cycle than G(2)/M. This may explain the failure to obtain tax ol radiosensitization with these cells and it may indicate that taxol has a multiplicity of actions with differences in effectiveness likely between cells of different origins.