Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line.
OBJECTIVE
To test the hypothesis that radiation-induced, transient G2/M arrest could potentially sensitize tumor cells to a subsequent, well-timed radiation dose.


METHODS
PC-3 human prostate cancer cells were treated using either radiotherapy or (186)Re-labeled hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment in different combinations. The resulting cell cycle shift and clonogenic cell death were analyzed by DNA flow cytometry and colony forming cell assay, respectively.


RESULTS
Radiation doses of 4 Gy and 8 Gy induced a transient G2/M arrest, with a maximum after approximately 16 h. The presence of 2 mM pentoxifylline effectively abrogated this radiation-induced G2 M arrest, confirming a cell-cycle checkpoint-mediated effect. A second dose of 4 Gy, timed at the height of the G2/M arrest, significantly increased clonogenic cell-kill compared to delivery after a suboptimal interval (10 h, 20 h or 25 h after the first radiation fraction). Moreover, timed second doses of 2 Gy, 3 Gy or 4 Gy yielded improved normalized treatment effects compared to non-pretreated control. Radionuclide treatment of PC-3 cells, using (186)Re-HEDP (0.74 MBq/ml and 1.48 MBq/ml; total dose: 4.1 and 8.2 Gy, respectively) also induced a dose-dependent G2/M accumulation, which sensitized the cells to a subsequent external radiation dose of 2 Gy or 4 Gy. The observed pattern of cell-cycle shift towards a predominance of the G2/M phase is in line with the lack of functional p53 in this cell line.


CONCLUSIONS
Radiation-induced cell-cycle shift was shown to effectively confer increased radiosensitivity to prostate tumor cells. Optimally timed combination of radiotherapy and radionuclide therapy could thus significantly increase treatment efficacy.
Geldof
Albert A
AA
Department of Nuclear Medicine, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. aa.geldof@vumc.nl
Plaizier
Marian A B D
MA
Duivenvoorden
Ilse
I
Ringelberg
Marieke
M
Versteegh
Richard T
RT
Newling
Don W W
DW
Teule
Gerrit J J
GJ
D002453:Cell Cycle / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects; D005434:Flow Cytometry; D016195:G2 Phase / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D008297:Male; D008938:Mitosis; D011471:Prostatic Neoplasms / Q000473:pathology*; D011829:Radiation Dosage; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured