Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line

Albert A. Geldof, Marian A B D Plaizier, Ilse Duivenvoorden, Marieke Ringelberg, Richard T. Versteegh, Don W W Newling, Gerrit J J Teule

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: 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 186Re-labeled hydroxyethylidene diphosphonate (186Re-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 186Re-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.

Original languageEnglish
Pages (from-to)175-182
Number of pages8
JournalJournal of Cancer Research and Clinical Oncology
Volume129
Issue number3
Publication statusPublished - 1 Mar 2003

Cite this

Geldof, A. A., Plaizier, M. A. B. D., Duivenvoorden, I., Ringelberg, M., Versteegh, R. T., Newling, D. W. W., & Teule, G. J. J. (2003). Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. Journal of Cancer Research and Clinical Oncology, 129(3), 175-182.
Geldof, Albert A. ; Plaizier, Marian A B D ; Duivenvoorden, Ilse ; Ringelberg, Marieke ; Versteegh, Richard T. ; Newling, Don W W ; Teule, Gerrit J J. / Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. In: Journal of Cancer Research and Clinical Oncology. 2003 ; Vol. 129, No. 3. pp. 175-182.
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abstract = "Purpose: 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 186Re-labeled hydroxyethylidene diphosphonate (186Re-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 186Re-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.",
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Geldof, AA, Plaizier, MABD, Duivenvoorden, I, Ringelberg, M, Versteegh, RT, Newling, DWW & Teule, GJJ 2003, 'Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line' Journal of Cancer Research and Clinical Oncology, vol. 129, no. 3, pp. 175-182.

Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. / Geldof, Albert A.; Plaizier, Marian A B D; Duivenvoorden, Ilse; Ringelberg, Marieke; Versteegh, Richard T.; Newling, Don W W; Teule, Gerrit J J.

In: Journal of Cancer Research and Clinical Oncology, Vol. 129, No. 3, 01.03.2003, p. 175-182.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line

AU - Geldof, Albert A.

AU - Plaizier, Marian A B D

AU - Duivenvoorden, Ilse

AU - Ringelberg, Marieke

AU - Versteegh, Richard T.

AU - Newling, Don W W

AU - Teule, Gerrit J J

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N2 - Purpose: 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 186Re-labeled hydroxyethylidene diphosphonate (186Re-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 186Re-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.

AB - Purpose: 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 186Re-labeled hydroxyethylidene diphosphonate (186Re-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 186Re-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.

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Geldof AA, Plaizier MABD, Duivenvoorden I, Ringelberg M, Versteegh RT, Newling DWW et al. Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. Journal of Cancer Research and Clinical Oncology. 2003 Mar 1;129(3):175-182.