CYTOTOXICITY OF THE ANTICANCER AGENTS CISPLATIN AND TAXOL DURING CELL-PROLIFERATION AND THE CELL-CYCLE

The overt effects of the anti-cancer drugs cisplatin (cis-DDP) and tax ol appear to be DNA modification and microtubule stabilization respect ively, yet the mechanisms by which these drugs elicit tumor cell death are not well understood. In this report cell sensitivities to cis-DDP and taxol were accurately determined as a function of cell proliferat ion and cell cycle stage. Quiescent fibroblasts restimulated to synchr onously enter the cell cycle become maximally sensitive to cis-DDP imm ediately preceding DNA synthesis, and resistance increases with onset of DNA synthesis. Mid-log proliferating cells were separated into prog ressive stages of the cell cycle by centrifugal elutriation or by doub le thymidine (dThd) block. Cells staged by either method are maximally sensitive to cis-DDP in G(1), just prior to the onset of DNA synthesi s and minimally sensitive in peak DNA synthesis, with entry into S pha se resulting in a 2-fold decrease in sensitivity. Cells that remained blocked at the G(1)/S phase boundary during cis-DDP treatment remain m aximally sensitive after release. Sensitivity to taxol increases at 2 points: transiently during transition of normal cells from quiescence to proliferation and steadily as proliferating cells progress from ear ly G(1) to late G(2). This 3-fold increase in taxol sensitivity throug h the cell cycle is rapidly reversed upon cell division. Synchronous c ells treated with either drug at points of maximum sensitivity initiat e apoptotic DNA fragmentation 12-14 hr post-exposure to drug. (C) 1994 Wiley-Liss, Inc.