2006
DOI: 10.1038/sj.onc.1209532
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Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

Abstract: Chk1 plays a crucial role in the DNA damage and replication checkpoints in vertebrates and may therefore be an important determinant of tumour cell responses to genotoxic anticancer drugs. To evaluate this concept we compared the effects of the nucleoside analogue 5-fluorouracil (5FU) on cell cycle progression and clonogenic survival in DT40 B-lymphoma cells with an isogenic mutant derivative in which Chk1 function was ablated by gene targeting. We show that 5FU activates Chk1 in wild-type DT40 cells and that … Show more

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Cited by 44 publications
(31 citation statements)
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“…The analysis of cell cycle perturbation after 5-FU treatment suggests that 24 h after the end with 5-FU an abrogation of S-phase checkpoint is observable and is much more marked in a p53 -/-and Chk1 -/-background. The observed effects are different from the ones reported by other studies assessing the effects of 5-FU treatment together with both pharmacologic (35) and siRNA inhibition of Chk1 (36) and in the DT40 cellular system Chk1 -/- (37). In the former cases, abrogation of Chk1 after 5-FU treatment caused a rapid onset of apoptosis without cell cycle progression specifically in cells with a S-phase DNA content or a progression to early M phase and induction of apoptosis, whereas in the latter cells undergo an impeded replication in the presence of 5-FU and then were completely blocked in the subsequent G 1 phase for a long time.…”
Section: Discussioncontrasting
confidence: 54%
“…The analysis of cell cycle perturbation after 5-FU treatment suggests that 24 h after the end with 5-FU an abrogation of S-phase checkpoint is observable and is much more marked in a p53 -/-and Chk1 -/-background. The observed effects are different from the ones reported by other studies assessing the effects of 5-FU treatment together with both pharmacologic (35) and siRNA inhibition of Chk1 (36) and in the DT40 cellular system Chk1 -/- (37). In the former cases, abrogation of Chk1 after 5-FU treatment caused a rapid onset of apoptosis without cell cycle progression specifically in cells with a S-phase DNA content or a progression to early M phase and induction of apoptosis, whereas in the latter cells undergo an impeded replication in the presence of 5-FU and then were completely blocked in the subsequent G 1 phase for a long time.…”
Section: Discussioncontrasting
confidence: 54%
“…[27][28][29][30] These observations suggest that activation of checkpoint signaling pathways may be an important factor is tumor resistance to genotoxic agents, and they have fueled intense interest in checkpoint inhibitors as potential antitumor agents. Here, we show that EXEL-9844, an orally available, small molecule Chk1 and Chk2 inhibitor causes effects on cells that are strikingly similar to deletion of the CHK1 gene or depletion of Chk1, and demonstrate that EXEL-9844 potently enhances gemcitabine activity.…”
Section: Discussionmentioning
confidence: 99%
“…The induction of γ-H2AX following RTX and FdUrd treatment is evident (Figure 4), yet the lack of difference between UNG proficient and UNG inhibited cells suggests that the more likely source of γ-H2AX induction is stalled or collapsed replication forks. It is known that altered S-phase progression occurs in cancer cells, and that defects in S-phase kinase signaling affects sensitivity to 5-FU [35][36][37]. Evaluation of such phenomena is particularly challenging in human cancer cell lines with known (and likely as yet unknown) defects in checkpoint signaling.…”
Section: Discussionmentioning
confidence: 99%