Radiosensitization of colon cancer cell lines by docetaxel: mechanisms of action.
The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxel is also an increasingly important drug for the treatment of cancer in concurrent radiotherapy protocols. However, the mechanisms of docetaxel radiosensitization are not fully understood. We have investigated the magnitude and mechanisms of docetaxel radiosensitization in vitro in four human colorectal cancer cell lines (SW480, SW707, SW48, and HT29) with widely differing radiosensitivities. Cell survival curves were generated for a range of docetaxel concentrations (5-20 nM) alone and for X-rays (1-5 Gy) +/- 10 or 20 nM docetaxel (for 24 h before irradiation). Cell cycle distributions and apoptotic frequencies were measured during the treatments. Sensitivity to docetaxel alone was similar in all cell lines and could be attributed to massive induction of apoptosis (60-80% by 24 h). Radiosensitivity varied widely; the surviving fractions at 2 Gy in the most resistant (HT29) and most sensitive (SW28) lines were 0.81 and 0.13, respectively. Exposure to 10 nM docetaxel induced a progressive accumulation of SW480, SW707, and SW48 cells in G2/M. After 24 h, 55-70% of the cells were in G2/M. It is likely, therefore, that accumulation in this radiosensitive phase of the cell cycle contributes significantly to radiosensitization by the drug.
Dunne
Amanda L
AL
School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1AS, UK.
Mothersill
Carmel
C
Robson
Tracy
T
Wilson
George D
GD
Hirst
David G
DG
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*
D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel