The Effects of G2-Phase Enrichment and Checkpoint Abrogation on Low-Dose Hyper-Radiosensitivity

Journal Article · Sun Aug 01 04:00:00 EDT 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.01.028· OSTI ID:21451147

Krueger, Sarah A; Wilson, George D ^[1]; Piasentin, Evano; Joiner, Michael C ^[2]; Marples, Brian ^[1]

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1. Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States)
2. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States)

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.

• OSTI ID: 21451147
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 5 Vol. 77; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AZINES
CELL CYCLE
CELL DIVISION
DNA DAMAGES
HETEROCYCLIC COMPOUNDS
MEDICINE
MITOSIS
NUCLEAR MEDICINE
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIMIDINES
RADIOLOGY
RADIOSENSITIVITY
RADIOTHERAPY
RIBOSIDES
SENSITIVITY
STRAND BREAKS
THERAPY
THYMIDINE