CHANGES IN RADIATION SURVIVAL-CURVE PARAMETERS IN HUMAN TUMOR AND RODENT CELLS EXPOSED TO PACLITAXEL (TAXOL(R))

Purpose: Late G(2) and M are the most radiosensitive phases of the cell cycle. Cells exposed to paclitaxel develop a cell cycle arrest in G(2)/M. These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor and rodent cell lines. Methods and Materials: The effect of paclitaxel on the radiation sensitivity of human breast (MCF-7) lung (A549), ovary (OVG-1) adenocarcinoma and Chinese hamster lung fibroblast V79 cells was determined with clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of the cells during irradiation. Survival curve parameters for all cell lines were determined with the use of a computer program which represents cell survival after radiation by a linear-quadratic model. Results: All cell lines developed a G(2)/M block after exposure to paclitaxel for 24 h. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The maximal sensitizer enhancement ratio (SER) of paclitaxel was 1.8 in MCF-7 cells, 1.6 in OVG-1 cells, and 1.7 in V79 cells. However, no concentration of paclitaxel was able to enhance the radiation sensitivity of A549 cells. Paclitaxel increased the linear (alpha) component of the radiation survival curves in all cell lines. The quadratic (beta) component was unaffected by paclitaxel in the rodent cells. High concentrations of paclitaxel (greater than or equal to 1000 nM) increased beta slightly in the human cell lines but there was considerable variation in the effect of paclitaxel on beta. The cells which were sensitized to radiation by paclitaxel had a relatively small baseline alpha component, while A549 cells had a large alpha component. Conclusion: We conclude that paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. Paclitaxel appears to cause radiosensitization mainly by increasing the cu component of radiation survival curves. Cells that normally have a relatively small alpha component should exhibit the most radiosensitization in response to paclitaxel while cells with a large cu component should show little or no radiosensitzation after paclitaxel treatment. Because the greatest effect of paclitaxel is on the linear component of radiation survival curves, these results indicate that paclitaxel may be an