Schedule-dependent interaction of paclitaxel (Taxol) and irradiation in vitro.

The optimal dose and schedule of paclitaxel in combination with irradiation have not been determined yet. The aim of this study was to compare the in vitro cytotoxicity and enhancement of radiation sensitization as a function of single vs. fractionated paclitaxel exposure. A fibroblast cell line (B14) in exponential growth phase was used. The clonogenic assay was applied to determine cell survival. Flow cytometric measurements were performed to study cell cycle DNA distribution. Cytotoxicity of Taxol was examined at concentrations varying from 2 to 50 microM. Single (1 x 0 microM) vs. fractionated (2 microM/day, days 1-5) exposure of Taxol was investigated. The combination of Taxol plus irradiation as single and fractionated treatment was accomplished with 10 microM Taxol on day 1 plus 10 Gy irradiation on day 1 vs. Taxol 2 microM/day, days 1-5, plus irradiation 2 Gy/day, days 1-5. One-, 9-, and 24-hr intervals between end of incubation and irradiation were defined. Control populations demonstrated an average plating efficiency of 93%. Single Taxol exposure showed an average clonogenic survival of 84%. No significant difference between concentrations varying from 2 to 50 microM was observed. Single dose irradiation (1 x 10 Gy) led to clonogenic survival of 3%. Single exposure of Taxol plus single dose irradiation led to clonogenic survival of 4%. Fractionated radiation showed an average clonogenic survival of 41%. Fractionated Taxol treatment led to an average clonogenic survival of 63%. The combination of fractionated Taxol treatment (2 microM/day, days 1-5) plus fractionated irradiation (2 Gy/day, days 1-5) showed an average clonogenic survival of 15%. No significant difference between the chosen intervals was demonstrated. Flow cytometric measurements did not indicate any significant alterations in cell cycle DNA distribution. In conclusion, the data demonstrate a potential beneficial effect by combining fractionated Taxol exposure with fractionated irradiation without evidence for G2/M arrest in DNA analysis.