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Cell cycle effects of gemcitabine
Author(s) -
Cappella Paolo,
Tomasoni Daniela,
Faretta Mario,
Lupi Monica,
Montalenti Francesco,
Viale Federica,
Banzato Fabio,
D'Incalci Maurizio,
Ubezio Paolo
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1351
Subject(s) - dna synthesis , cisplatin , gemcitabine , cell cycle , sulforhodamine b , cytotoxicity , flow cytometry , chemistry , bromodeoxyuridine , biology , cell growth , dna , in vitro , microbiology and biotechnology , cell , biochemistry , cancer , chemotherapy , genetics
Gemcitabine (2′,2′‐difluoro‐2′‐deoxycytidine, or dFdC) is a promising anticancer agent with demonstrated clinical activity in solid tumours currently undergoing clinical trials. Despite extensive studies on the biochemical mechanism of action, cell cycle perturbations induced by dFdC have not yet been thoroughly investigated, apart from the expected inhibition of DNA synthesis. The aim of our study was to clarify whether cell population kinetics is a vital factor in the cytotoxicity of dFdC in single or repeated treatments and in the dFdC‐cisplatin combination. Ovarian cancer cells growing in vitro were treated with dFdC for 1 hr in a range of concentrations from 10 nM to 10 μM. Cell kinetics was investigated by DNA‐bromodeoxyuridine flow cytometry, using different experimental protocols to measure either the time course of DNA‐synthesis inhibition or the fate of cells in G 1 , S or G 2 M at the time of dFdC treatment or 24 hr later. A modified sulforhodamine B test was used to assess the growth inhibition caused by dFdC given alone or with cisplatin. Although dFdC promptly inhibited DNA synthesis, cytotoxicity on proliferating cells was not specific for cells initially in the S phase. DNA synthesis was restored after a G 1 block of variable, dose‐dependent length, but recycling cells were intercepted at the subsequent checkpoints, resulting in delays in the G 2 M and G 1 phases. The activity of repeated treatment with dFdC+dFdC or dFdC+cisplatin was highly dependent on the interval length between them. These results suggest that the kinetics of cell recycling from a first dFdC treatment strongly affects the outcome of a second treatment with either dFdC itself or cisplatin. © 2001 Wiley‐Liss, Inc.