The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity

Sarah A. Krueger, George D. Wilson, Evano Piasentin, Michael C. Joiner, Brian Marples

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Purpose: An association between low-dose hyper-radiosensitivity (HRS) and the "early" G2/M checkpoint has been established. An improved molecular understanding of the temporal dynamics of this relationship is needed before clinical translation can be considered. This study was conducted to characterize the dose response of the early G2/M checkpoint and then determine whether low-dose radiation sensitivity could be increased by synchronization or chemical inhibition of the cell cycle. Methods and Materials: Two related cell lines with disparate HRS status were used (MR4 and 3.7 cells). A double-thymidine block technique was developed to enrich the G2-phase population. Clonogenic cell survival, radiation-induced G2-phase cell cycle arrest, and deoxyribonucleic acid double-strand break repair were measured in the presence and absence of inhibitors to G2-phase checkpoint proteins. Results: For MR4 cells, the dose required to overcome the HRS response (approximately 0.2 Gy) corresponded with that needed for the activation of the early G2/M checkpoint. As hypothesized, enriching the number of G2-phase cells in the population resulted in an enhanced HRS response, because a greater proportion of radiation-damaged cells evaded the early G2/M checkpoint and entered mitosis with unrepaired deoxyribonucleic acid double-strand breaks. Likewise, abrogation of the checkpoint by inhibition of Chk1 and Chk2 also increased low-dose radiosensitivity. These effects were not evident in 3.7 cells. Conclusions: The data confirm that HRS is linked to the early G2/M checkpoint through the damage response of G2-phase cells. Low-dose radiosensitivity could be increased by manipulating the transition of radiation-damaged G2-phase cells into mitosis. This provides a rationale for combining low-dose radiation therapy with chemical synchronization techniques to improve increased radiosensitivity.

Original languageEnglish (US)
Pages (from-to)1509-1517
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume77
Issue number5
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Fingerprint

G2 Phase Cell Cycle Checkpoints
Radiation Tolerance
radiation tolerance
G2 Phase
dosage
cells
mitosis
radiation
strands
Radiation
Mitosis
synchronism
deoxyribonucleic acid
thymidine
cycles
DNA
cultured cells
inhibitors
radiation therapy
proportion

Keywords

  • Cell cycle
  • Chk1
  • Chk2
  • G2 checkpoint arrest
  • Ionizing radiation
  • Low dose

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research

Cite this

The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity. / Krueger, Sarah A.; Wilson, George D.; Piasentin, Evano; Joiner, Michael C.; Marples, Brian.

In: International Journal of Radiation Oncology Biology Physics, Vol. 77, No. 5, 01.08.2010, p. 1509-1517.

Research output: Contribution to journalArticle

Krueger, Sarah A. ; Wilson, George D. ; Piasentin, Evano ; Joiner, Michael C. ; Marples, Brian. / The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity. In: International Journal of Radiation Oncology Biology Physics. 2010 ; Vol. 77, No. 5. pp. 1509-1517.
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