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.
Strunz
A M
AM
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
Peschke
P
P
Waldeck
W
W
Ehemann
V
V
Kissel
M
M
Debus
J
J
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