Alterations in the Progression of Cells through the Cell Cycle after Exposure to Alpha Particles or Gamma Rays

Abstract

A G1-phase delay after exposure to alpha particles has not been report ed previously, perhaps because immortalized cell lines or cell lines from tumor cells were used in past studies. Therefore, we compared the effects of alpha particles (0.19 or 0.57 Gy) and approximately equitoxic doses of gamma rays (2 or 4 Gy) on progression of cells through the cell cycle in normal human skin fibroblasts. Cell cycle analyses were performed using flow cytometry by measuring incorporation of bromodeoxyuridine (BrdUrd) in each phase of the cell cycle up to 44 h after irradiation. We observed an alpha-particle-induced G1-phase delay in human skin fibroblasts even at the lowest dose, 0.19 Gy. At equitoxic doses, more pronounced and persistent G1-phase delays and arrests were observed in gamma-irradiated cultures in that increased fractions of the G1-phase cells remained BrdUrd- over the course of the study after gamma-ray exposure compared to cells exposed to alpha particles. In addition, G1-phase cells that became BrdUrd+ after gamma irradiation re-arrested in G1 phase, whereas BrdUrd+ G1-phase cells in alpha-particle-irradiated cultures continued cycling. In contrast, comparable percentages of cells were delayed in G2 phase after either alpha-particle or gamma irradiation. Both gamma and alpha-particle irradiation caused increases in cellular p53 and p2lCip1 shortly after the exposures, which suggests that the G1-phase delay that occurs in response to alpha-particle irradiation is dependent on p53 like the initial G1-phase delay induced by gamma rays.

Targeted use of Alpha Particles: Current Status in Cancer Therapeutics

“…The double strand breaks created by alpha particle radiation have been found to be highly complex, more resistant to normal repair, and thus more genotoxic than double strand breaks caused by other modalities [11]. This is thought to be due to alpha particles tendency to create dense tracks of ionization that create clusters of DNA damage, whereas the damage caused by gamma radiation is more sparsely distributed [12]. The maximum rate of double-stranded DNA breaks occurs at LETs of 100-200 keV/μm, a range that includes the LET of most alpha particles [13].…”

“…Low LET radiation, including gamma radiation, has been found to cause a prolonged arrest of the cell cycle in G1 and G2, which allows the cells time to repair DNA damage. The cell cycle arrest caused by alpha particle radiation is shorter, and more difficult to repair, thus alpha particles are more effective at inducing cellular death [12].…”

Modeling Dose Deposition and DNA Damage Due to Low-Energy β–Emitters

“…This arrest can be long-term or even permanent (Linke et al, 1997;Savell et al, 2001) and there is also evidence that irradiation in G 0 can render cells less responsive to biochemical mitogens that act to drive cells through the cell cycle (Duncan and Lawrence, 1991); this lack of responsiveness is probably associated with G 1 arrest or with the onset of programmed cell death (apoptosis). In some cases these responses have been linked with the activity of particular genes/proteins, eg p53 and p21 (Gadbois et al, 1996;Linke et al, 1997). Cells that, after an initial delay, escape the G 1 block can also arrest later in the cycle (Gadbois et al, 1996).…”

“…In some cases these responses have been linked with the activity of particular genes/proteins, eg p53 and p21 (Gadbois et al, 1996;Linke et al, 1997). Cells that, after an initial delay, escape the G 1 block can also arrest later in the cycle (Gadbois et al, 1996). There is also good evidence for high cellular repair capacity in the G 0 phase as judged by post-irradiation holding of cells in the G 0 phase prior to mitogenic stimulation (UNSCEAR, 2000).…”

“…The Committee then examined a number of reports which stated that available studies provided little evidence for the proposition that low dose irradiation of quiescent (G 0 /G 1 ) cells triggered progression through the cell cycle (Duncan and Lawrence, 1991;Gadbois et al, 1996;Linke et al, 1997;Savell et al, 2001). On the contrary, much evidence showed that cell cycle checkpoints inhibited cells from progressing through the cell cycle while they repaired DNA damage.…”