Open AccessDynamics 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
Author(s) -
Tavecchio M.,
Natoli C.,
Ubezio P.,
Erba E.,
D’Incalci M.
Publication year - 2007
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/j.1365-2184.2007.00469.x
Subject(s) - trabectedin , nucleotide excision repair , dna repair , dna damage , cell cycle , cell culture , chemistry , microbiology and biotechnology , cell , cancer research , biology , dna , biochemistry , genetics , medicine , soft tissue , soft tissue sarcoma , pathology
. 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 G 2 + 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 G 1 and G 2 + M first experienced a G 1 block, while those exposed in S phase were delayed in S and G 2 + M phases but eventually divided. In the presence of functional NER, exit from the G 1 block was faster; then, cells progressed slowly through S phase and were subsequently blocked in G 2 + M phase. This G 2 + 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 G 1 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 G 1 and G 2 + M phases.