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 cel l cycle. Cells exposed to paclitaxel develop a cell cycle arrest in G( 2)/M. These studies were performed to assess the in vitro radiosensiti zation properties of paclitaxel in human tumor and rodent cell lines. Methods and Materials: The effect of paclitaxel on the radiation sensi tivity of human breast (MCF-7) lung (A549), ovary (OVG-1) adenocarcino ma and Chinese hamster lung fibroblast V79 cells was determined with c lonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of the cells during irradiation. Surviv al 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 b lock after exposure to paclitaxel for 24 h. However, the degree of rad iosensitization produced by paclitaxel varied among the cell lines. Th e 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 con centration of paclitaxel was able to enhance the radiation sensitivity of A549 cells. Paclitaxel increased the linear (alpha) component of t he radiation survival curves in all cell lines. The quadratic (beta) c omponent was unaffected by paclitaxel in the rodent cells. High concen trations of paclitaxel (greater than or equal to 1000 nM) increased be ta slightly in the human cell lines but there was considerable variati on in the effect of paclitaxel on beta. The cells which were sensitize d to radiation by paclitaxel had a relatively small baseline alpha com ponent, while A549 cells had a large alpha component. Conclusion: We c onclude that paclitaxel is a modest radiosensitizer in some, but not a ll, human tumor cells. Paclitaxel appears to cause radiosensitization mainly by increasing the cu component of radiation survival curves. Ce lls that normally have a relatively small alpha component should exhib it the most radiosensitization in response to paclitaxel while cells w ith a large cu component should show little or no radiosensitzation af ter paclitaxel treatment. Because the greatest effect of paclitaxel is on the linear component of radiation survival curves, these results i ndicate that paclitaxel may be an