Abstract
Topotecan (TPT) is a topoisomerase I inhibitor, and like the other drugs of this family, it is believed to act in a specific way on cells in S phase at the time of treatment. Exploiting a new method, coupling a particular experimental plan with computer simulation, a complete quantitative study of the time dependence and dose dependence of the activity of cell cycle controls has become feasible, and the overall scenario of events after treatment can be reconstructed in detail. We were able to demonstrate that the response of an ovarian cancer cell line to 1 h of treatment with TPT is not limited to inhibition of DNA synthesis, leading to cell death, but involves G1 and G2-M checkpoints. G1 and G2-M block, recycling, and death follow specific dose-dependent kinetics, lasting no less than 3 days after treatment. We also found that cells treated outside S phase contribute significantly to the overall activity. The utility of this analysis was demonstrated by reproducing more complex treatment schemes in which low TPT concentrations were applied for 1 h three times at 24-h intervals. In this case, the simulation clarified the origin of the auto-potentiation observed with repeated 0.2 μm treatments, in which the cytotoxicity, particularly against S-phase cells, was higher than the cytotoxicity in cells treated with 10 μm only once. We believe that this approach will help us to understand the complexity and heterogeneity of the response of a cell population to a drug challenge and could help us to establish the rationale for drug scheduling or drug combinations.
| Original language | English |
|---|---|
| Pages (from-to) | 2825-2832 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 64 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Apr 15 2004 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Cytostatic and Cytotoxic Effects of Topotecan Decoded by a Novel Mathematical Simulation Approach. / Lupi, Monica; Matera, Giada; Branduardi, Davide; D'Incalci, Maurizio; Ubezio, Paolo.
In: Cancer Research, Vol. 64, No. 8, 15.04.2004, p. 2825-2832.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cytostatic and Cytotoxic Effects of Topotecan Decoded by a Novel Mathematical Simulation Approach
AU - Lupi, Monica
AU - Matera, Giada
AU - Branduardi, Davide
AU - D'Incalci, Maurizio
AU - Ubezio, Paolo
PY - 2004/4/15
Y1 - 2004/4/15
N2 - Topotecan (TPT) is a topoisomerase I inhibitor, and like the other drugs of this family, it is believed to act in a specific way on cells in S phase at the time of treatment. Exploiting a new method, coupling a particular experimental plan with computer simulation, a complete quantitative study of the time dependence and dose dependence of the activity of cell cycle controls has become feasible, and the overall scenario of events after treatment can be reconstructed in detail. We were able to demonstrate that the response of an ovarian cancer cell line to 1 h of treatment with TPT is not limited to inhibition of DNA synthesis, leading to cell death, but involves G1 and G2-M checkpoints. G1 and G2-M block, recycling, and death follow specific dose-dependent kinetics, lasting no less than 3 days after treatment. We also found that cells treated outside S phase contribute significantly to the overall activity. The utility of this analysis was demonstrated by reproducing more complex treatment schemes in which low TPT concentrations were applied for 1 h three times at 24-h intervals. In this case, the simulation clarified the origin of the auto-potentiation observed with repeated 0.2 μm treatments, in which the cytotoxicity, particularly against S-phase cells, was higher than the cytotoxicity in cells treated with 10 μm only once. We believe that this approach will help us to understand the complexity and heterogeneity of the response of a cell population to a drug challenge and could help us to establish the rationale for drug scheduling or drug combinations.
AB - Topotecan (TPT) is a topoisomerase I inhibitor, and like the other drugs of this family, it is believed to act in a specific way on cells in S phase at the time of treatment. Exploiting a new method, coupling a particular experimental plan with computer simulation, a complete quantitative study of the time dependence and dose dependence of the activity of cell cycle controls has become feasible, and the overall scenario of events after treatment can be reconstructed in detail. We were able to demonstrate that the response of an ovarian cancer cell line to 1 h of treatment with TPT is not limited to inhibition of DNA synthesis, leading to cell death, but involves G1 and G2-M checkpoints. G1 and G2-M block, recycling, and death follow specific dose-dependent kinetics, lasting no less than 3 days after treatment. We also found that cells treated outside S phase contribute significantly to the overall activity. The utility of this analysis was demonstrated by reproducing more complex treatment schemes in which low TPT concentrations were applied for 1 h three times at 24-h intervals. In this case, the simulation clarified the origin of the auto-potentiation observed with repeated 0.2 μm treatments, in which the cytotoxicity, particularly against S-phase cells, was higher than the cytotoxicity in cells treated with 10 μm only once. We believe that this approach will help us to understand the complexity and heterogeneity of the response of a cell population to a drug challenge and could help us to establish the rationale for drug scheduling or drug combinations.
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U2 - 10.1158/0008-5472.CAN-03-3810
DO - 10.1158/0008-5472.CAN-03-3810
M3 - Article
VL - 64
SP - 2825
EP - 2832
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 8
ER -