Preferential radiosensitization in p53-mutated human tumour cell lines by pentoxifylline-mediated disruption of the G2/M checkpoint control.
OBJECTIVE
There is evidence that the duration of the G2/M delay following irradiation is correlated with cell survival. We studied the radiosensitizing potential of pentoxifylline (PTX) and the PTX-mediated modulation of cell-cycle progression dependent on the p53 status of various human tumour cell lines.


METHODS
The cellular radiosensitivity of human MCF-7 (wild-type p53) and HT-29 (p53-defective) tumour cells, which were exposed to PTX (2 mM) immediately after gamma-irradiation was determined by colony forming assay. The influence on cell cycle progression after irradiation (6 Gy) was assessed by flow cytometric analysis using p53 wild-type MCF-7 and HPR600 cells, and p53-defective HT-29 and WiDr cells.


RESULTS
Clonogenic survival assays up to 8 Gy demonstrated that p53-defective HT-29 cells (sensitizer enhancement ratio [SER]=1.54) were sensitized by PTX (2 mM) to a significantly higher degree than p53 wild-type MCF-7 (SER=1.14) cells. Exposure of irradiated (6 Gy) cells to PTX (2 mM) resulted in abrogation of the radiation-induced G2/M arrest in the p53-defective HT-29 and WiDr cells, whereas the p53 wild-type-expressing MCF-7 and HPR600 cells showed less significant impairment of the G2/M checkpoint. In HT-29 cells, the rate of transition into mitosis was even higher than in the sham-treated control cells. G2/M abrogation was accompanied by an increase of apoptosis only in HPR600 cells.


CONCLUSIONS
Since PTX was less effective in cells expressing intact p53, the application of PTX suggests a promising strategy of pharmacological disruption of the G2/M checkpoint control by which preferentially radiation-resistant tumours with defective p53 function might be rendered more sensitive to ionizing radiation.
Radiologische Diagnostik und Therapie, Abteilung Strahlentherapeutische Onkologie Abteilung Biophysik der Makromoleküle, Deutsches Krebsforschungzentrum (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. a.strunz@dkfz.de
A M
AM
Strunz
P
P
Peschke
W
W
Waldeck
V
V
Ehemann
M
M
Kissel
J
J
Debus
D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D016195:G2 Phase / Q000528:radiation effects; D006801:Humans; D007700:Kinetics; D008938:Mitosis / Q000528:radiation effects; D010431:Pentoxifylline / Q000494:pharmacology*; D011836:Radiation Tolerance; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D010431:Pentoxifylline