Cellular Determinants of Sensitivity and Resistance to DNA Topoisomerase Inhibitors

Pommier, ﻿Yves; Pharm, D; Fesen, Mark R.; Fujimori, A.; Bertrand, Richard; Solary, Éric; Kohlhagen, Glenda; Kohn, Kurt W.

doi:10.3109/07357909409021413

Cited by 197 publications

(108 citation statements)

References 66 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…The associated proteins may prevent PARP binding to the DNA strand break, and hence PARP activation. In contrast, it has been proposed that collision between the DNA replication fork and camptothecin-topoisomerase I complex produces a proteinassociated single-strand break and a non-protein-associated double-strand break 3' to the complex, (Pommier et al, 1994). Indeed, DNA double-strand ends have been detected in extracts from human colon carcinoma cells treated with camptothecin (Strumberg et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

et al. 2001

View full text Add to dashboard Cite

The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

show abstract

Section: Discussionmentioning

confidence: 99%

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Hence, camptothecin converts topoisomerase I from an essential enzyme into a DNA damaging protein when replication complexes collide with the drug-stabilized cleavage complexes. [10][11][12][13][14][15][16] The mechanism of cytoxicity to camptothecin is not yet clear. Studies showed that two factors were related to camptothecin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…This DNA-damaging mechanism, at least in some cell types, accounts for the maximum toxicity of camptothecin during the S phase. [14][15][16] This toxicity mechanism has been shown to be protectable by aphidicolin, an inhibitor of replicative DNA polymerases. 15,34 Second, studies showed that the camptothecin sensitivity is also correlated with topoisomerse I levels, altered topoisomerase I gene, or reduced topoisomerase I Figure 7 In vivo antitumor effect of the combination treatment of adenovirus-E2F-1 (Ad5CMV-E2F-1) and camptothecin.…”

Section: Discussionmentioning

confidence: 99%

“…Camptothecin stabilizes cleavage complexes, resulting in single-strand DNA breaks that cannot be religated in the presence of the drug. [10][11][12][13][14][15]47 It has been reported that camptothecin cytotoxicity is related to two types of defects: during S phase, accumulation of damaged replicons and failure to complete elongation of replicating DNA; and during G2 phase, deficiency to downregulate cyclin B/cdc2 kinase and reduced G2 arrest. 34 So it is possible that the topoisomerase I inhibition coupled with DNA damage and unregulated E2F-1 activity may also trigger an S-phase cell cycle checkpoint and arrest cell cycle at G2 phase, followed by apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…This DNA damaging mechanism, at least in some cell types, accounts for the maximum toxicity of camptothecin during the S phase of the cell cycle. [14][15][16] Therefore, topoisomerase I poisons are considered to be S-phase-specific agents. Sensitivity to topoisomerase I inhibitors is also related to intracellular topoisomerase I levels.…”

mentioning

confidence: 99%

See 2 more Smart Citations

E2F-1 overexpression sensitizes colorectal cancer cells to camptothecin

2003

View full text Add to dashboard Cite

Topoisomerase I inhibitors have been shown to have clinical activity against human colorectal cancer. Previous studies showed that the cytotoxicity of camptothecin, a topoisomerase I inhibitor, occurs mainly in the S -phase of the cell cycle and is protectable by aphidicolin, an inhibitor of replicative DNA polymerase in some camptothecin-sensitive colorectal cells. Transcription factor E2F-1 regulates the G1/S transition, and recent studies have shown that E2F-1 potentiated the cytotoxicity of some cell-cycle-related drugs. Therefore, the present study was designed to investigate the effect of adenovirus-mediated E2F-1 gene transfer on chemosensitivity of colorectal cancer to camptothecin, in vitro and in vivo. Two human colorectal cancer cells, SW620 (mutant p53) and RKO (wildtype p53), were treated with camptothecin, alone or in combination with adenoviral vectors expressing b-galactosidase (Ad-LacZ), or E2F-1 (Ad-E2F-1). E2F-1 overexpression was confirmed by Western blot analysis. Ad-E2F-1 gene transfer at low doses (less than the LD 20 dose) markedly increased the sensitivity of human colorectal cancer cells to camptothecin in vitro, which is because of induction of apoptosis. Aphidicolin did not have any protective effect on the Ad-E2F-1/camptothecin-mediated cytotoxicity. The level of topoisomerase I expression was not affected by combination treatment as well, suggesting that DNA replication and topoisomerase I activity may not account for the molecular mechanism of cell killing in response to Ad-E2F-1/camptothecin treatment. Fas and Fas ligand expression were not altered by treatment with camptothecin and/or Ad-E2F-1. Moreover, combination of camptothecin and Ad-E2F-1 has an additive antitumor effect in an in vivo nude mouse xenograft model. When combined with camptothecin, E2F-1 adenovirus therapy resulted in a 95.7% decrease in tumor size compared to control groups (Po.05). These results suggest a chemosensitization strategy that may have clinical utility in human colorectal cancer.

show abstract

Glucose-regulated stresses induce resistance to camptothecin in human cancer cells

1996

View full text Add to dashboard Cite

show abstract

Cellular Determinants of Sensitivity and Resistance to DNA Topoisomerase Inhibitors

Cited by 197 publications

References 66 publications

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

E2F-1 overexpression sensitizes colorectal cancer cells to camptothecin

Glucose-regulated stresses induce resistance to camptothecin in human cancer cells

Contact Info

Product

Resources

About