Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach
(2007) In Cell Proliferation 40(6). p.885-904- Abstract
OBJECTIVES: Trabectedin (ET-743, Yondelis) is a natural marine product, with antitumour activity, currently in phase II/III clinical trials. Previous studies have shown that cells hypersensitive to ultraviolet (UV)-rays because of nucleotide excision repair (NER) deficiency, were resistant to trabectedin. The purpose of this study was to investigate whether this resistance was associated with different drug-induced cell cycle perturbations.
MATERIALS AND METHODS: An isogenic NER-proficient cellular system (CHO-AA8) and a NER-deficient one (CHO-UV-96), lacking functional ERCC-1, were studied. Flow cytometric assays showed progressive accumulation of cells in G2 + M phase in NER-proficient but not in NER-deficient cells. Applying a... (More)
OBJECTIVES: Trabectedin (ET-743, Yondelis) is a natural marine product, with antitumour activity, currently in phase II/III clinical trials. Previous studies have shown that cells hypersensitive to ultraviolet (UV)-rays because of nucleotide excision repair (NER) deficiency, were resistant to trabectedin. The purpose of this study was to investigate whether this resistance was associated with different drug-induced cell cycle perturbations.
MATERIALS AND METHODS: An isogenic NER-proficient cellular system (CHO-AA8) and a NER-deficient one (CHO-UV-96), lacking functional ERCC-1, were studied. Flow cytometric assays showed progressive accumulation of cells in G2 + M phase in NER-proficient but not in NER-deficient cells. Applying a computer simulation method, we realized that the dynamics of the cell cycle perturbations in all phases were complex.
RESULTS: Cells exposed to trabectedin during G1 and G2 + M first experienced a G1 block, while those exposed in S phase were delayed in S and G2 + M phases but eventually divided. In the presence of functional NER, exit from the G1 block was faster; then, cells progressed slowly through S phase and were subsequently blocked in G2 + M phase. This G2 + M processing of trabectedin-induced damage in NER-proficient cells was unable to restore cell cycling, suggesting a difficulty in repairing the damage.
CONCLUSIONS: This might be due either to important damage left unrepaired by previous G1 repair, or that NER activity itself caused DNA damage, or both. We speculate that in UV-96 cells repair mechanisms other than NER are activated both in G1 and G2 + M phases.
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- author
- Tavecchio, M LU ; Natoli, C ; Ubezio, P ; Erba, Eugenio and D'Incalci, Maurizio
- publishing date
- 2007-12
- type
- Contribution to journal
- publication status
- published
- keywords
- Animals, Bromodeoxyuridine, CHO Cells, Cell Count, Cell Cycle, Cell Death, Cell Line, Cell Proliferation, Colony-Forming Units Assay, Computer Simulation, Cricetinae, Cricetulus, DNA, DNA Repair, Dioxoles, Flow Cytometry, G1 Phase, G2 Phase, Models, Biological, S Phase, Tetrahydroisoquinolines, Journal Article, Research Support, Non-U.S. Gov't
- in
- Cell Proliferation
- volume
- 40
- issue
- 6
- pages
- 885 - 904
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:36248974108
- pmid:18021177
- ISSN
- 1365-2184
- DOI
- 10.1111/j.1365-2184.2007.00469.x
- language
- English
- LU publication?
- no
- id
- 21cb4737-f531-4250-a70e-909198eb5aa6
- date added to LUP
- 2017-03-07 09:15:06
- date last changed
- 2024-02-29 10:53:49
@article{21cb4737-f531-4250-a70e-909198eb5aa6,
abstract = {{<p>OBJECTIVES: Trabectedin (ET-743, Yondelis) is a natural marine product, with antitumour activity, currently in phase II/III clinical trials. Previous studies have shown that cells hypersensitive to ultraviolet (UV)-rays because of nucleotide excision repair (NER) deficiency, were resistant to trabectedin. The purpose of this study was to investigate whether this resistance was associated with different drug-induced cell cycle perturbations.</p><p>MATERIALS AND METHODS: An isogenic NER-proficient cellular system (CHO-AA8) and a NER-deficient one (CHO-UV-96), lacking functional ERCC-1, were studied. Flow cytometric assays showed progressive accumulation of cells in G2 + M phase in NER-proficient but not in NER-deficient cells. Applying a computer simulation method, we realized that the dynamics of the cell cycle perturbations in all phases were complex.</p><p>RESULTS: Cells exposed to trabectedin during G1 and G2 + M first experienced a G1 block, while those exposed in S phase were delayed in S and G2 + M phases but eventually divided. In the presence of functional NER, exit from the G1 block was faster; then, cells progressed slowly through S phase and were subsequently blocked in G2 + M phase. This G2 + M processing of trabectedin-induced damage in NER-proficient cells was unable to restore cell cycling, suggesting a difficulty in repairing the damage.</p><p>CONCLUSIONS: This might be due either to important damage left unrepaired by previous G1 repair, or that NER activity itself caused DNA damage, or both. We speculate that in UV-96 cells repair mechanisms other than NER are activated both in G1 and G2 + M phases.</p>}},
author = {{Tavecchio, M and Natoli, C and Ubezio, P and Erba, Eugenio and D'Incalci, Maurizio}},
issn = {{1365-2184}},
keywords = {{Animals; Bromodeoxyuridine; CHO Cells; Cell Count; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Colony-Forming Units Assay; Computer Simulation; Cricetinae; Cricetulus; DNA; DNA Repair; Dioxoles; Flow Cytometry; G1 Phase; G2 Phase; Models, Biological; S Phase; Tetrahydroisoquinolines; Journal Article; Research Support, Non-U.S. Gov't}},
language = {{eng}},
number = {{6}},
pages = {{885--904}},
publisher = {{Wiley-Blackwell}},
series = {{Cell Proliferation}},
title = {{Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach}},
url = {{http://dx.doi.org/10.1111/j.1365-2184.2007.00469.x}},
doi = {{10.1111/j.1365-2184.2007.00469.x}},
volume = {{40}},
year = {{2007}},
}