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Tracking the cell cycle origins for escape from topotecan action by breast cancer cells.

Feeney GP, Errington RJ, Wiltshire M, Marquez N, Chappell SC, Smith PJ - Br. J. Cancer (2003)

Bottom Line: This implies that cancer cells that are not actively replicating DNA could resist the effects of the drug.Topotecan prevented all mitoses from S-phase cells and G1 cells (half-maximal effects at 0.14 microM and 0.96 microM, respectively).No dose of topotecan completely prevented mitosis among G2 cells, and at saturating doses of topotecan about half the cells of G2 origin continued dividing (the half-maximal effects was at 0.31 microM).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathalogy, University of Wales College of Medicine, Cardiff, UK.

ABSTRACT
The anticancer agent topotecan is considered to be S-phase specific. This implies that cancer cells that are not actively replicating DNA could resist the effects of the drug. The cycle specificity of topotecan action was investigated in MCF-7 cells, using time-lapse microscopy to link the initial cell cycle position during acute exposures to topotecan with the antiproliferative consequences for individual cells. The bioactive dose range (0.5-10 microM) for 1-h topotecan exposures was defined by rapid drug delivery and topoisomerase I trapping. Topotecan caused pan-cycle induction and activation of p53. Lineage analysis of the time-lapse sequences identified cells initially in S-phase and G2, and defined the time to mitosis for cells originating from G2, S-phase and G1. Topotecan prevented all mitoses from S-phase cells and G1 cells (half-maximal effects at 0.14 microM and 0.96 microM, respectively). No dose of topotecan completely prevented mitosis among G2 cells, and at saturating doses of topotecan about half the cells of G2 origin continued dividing (the half-maximal effects was at 0.31 microM). Overall, topotecan differentially targeted G1-, S- and G2-phase cells, but many G2 cells were resistant to topotecan, presenting a clear route for cell cycle-mediated drug resistance.

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Dose–response curves for the effects of topotecan upon G2, S-phase and G1 cells, respectively, are shown. Based upon the expected mitosis rate, the effects of 1-h incubations with topotecan (0–10 μM) upon mitosis rates for (A) G2 cells (R2=0.56) (B) S-phase cells (R2=0.99) and (C) G1 cells (R2=0.93) are shown. The subsequent residual proliferative capacity of the whole-cell populations after all first cycle divisions is shown in (D). Estimates of maximal decrease in mitosis rate (response, Mmax) and the topotecan dose required to achieve half-maximal response D1/2 were made from curves fitted to the data points: G2 Mmax=55.76%, D1/2=0.31 μM; S-phase Mmax=−8.1%, D1/2=0.14 μM; G1 Mmax=−23.9%, D1/2=0.96 μM.
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fig3: Dose–response curves for the effects of topotecan upon G2, S-phase and G1 cells, respectively, are shown. Based upon the expected mitosis rate, the effects of 1-h incubations with topotecan (0–10 μM) upon mitosis rates for (A) G2 cells (R2=0.56) (B) S-phase cells (R2=0.99) and (C) G1 cells (R2=0.93) are shown. The subsequent residual proliferative capacity of the whole-cell populations after all first cycle divisions is shown in (D). Estimates of maximal decrease in mitosis rate (response, Mmax) and the topotecan dose required to achieve half-maximal response D1/2 were made from curves fitted to the data points: G2 Mmax=55.76%, D1/2=0.31 μM; S-phase Mmax=−8.1%, D1/2=0.14 μM; G1 Mmax=−23.9%, D1/2=0.96 μM.

Mentions: Identification of the time periods when G2, S-phase then G1 cells would be expected to deliver to mitosis, derived from unperturbed untreated control cell data meant that the mitosis rates for cells exposed to topotecan (0.5–10 μM) could be measured separately for G2, S-phase and G1 originating cells (Figure 3Figure 3


Tracking the cell cycle origins for escape from topotecan action by breast cancer cells.

Feeney GP, Errington RJ, Wiltshire M, Marquez N, Chappell SC, Smith PJ - Br. J. Cancer (2003)

Dose–response curves for the effects of topotecan upon G2, S-phase and G1 cells, respectively, are shown. Based upon the expected mitosis rate, the effects of 1-h incubations with topotecan (0–10 μM) upon mitosis rates for (A) G2 cells (R2=0.56) (B) S-phase cells (R2=0.99) and (C) G1 cells (R2=0.93) are shown. The subsequent residual proliferative capacity of the whole-cell populations after all first cycle divisions is shown in (D). Estimates of maximal decrease in mitosis rate (response, Mmax) and the topotecan dose required to achieve half-maximal response D1/2 were made from curves fitted to the data points: G2 Mmax=55.76%, D1/2=0.31 μM; S-phase Mmax=−8.1%, D1/2=0.14 μM; G1 Mmax=−23.9%, D1/2=0.96 μM.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747574&req=5

fig3: Dose–response curves for the effects of topotecan upon G2, S-phase and G1 cells, respectively, are shown. Based upon the expected mitosis rate, the effects of 1-h incubations with topotecan (0–10 μM) upon mitosis rates for (A) G2 cells (R2=0.56) (B) S-phase cells (R2=0.99) and (C) G1 cells (R2=0.93) are shown. The subsequent residual proliferative capacity of the whole-cell populations after all first cycle divisions is shown in (D). Estimates of maximal decrease in mitosis rate (response, Mmax) and the topotecan dose required to achieve half-maximal response D1/2 were made from curves fitted to the data points: G2 Mmax=55.76%, D1/2=0.31 μM; S-phase Mmax=−8.1%, D1/2=0.14 μM; G1 Mmax=−23.9%, D1/2=0.96 μM.
Mentions: Identification of the time periods when G2, S-phase then G1 cells would be expected to deliver to mitosis, derived from unperturbed untreated control cell data meant that the mitosis rates for cells exposed to topotecan (0.5–10 μM) could be measured separately for G2, S-phase and G1 originating cells (Figure 3Figure 3

Bottom Line: This implies that cancer cells that are not actively replicating DNA could resist the effects of the drug.Topotecan prevented all mitoses from S-phase cells and G1 cells (half-maximal effects at 0.14 microM and 0.96 microM, respectively).No dose of topotecan completely prevented mitosis among G2 cells, and at saturating doses of topotecan about half the cells of G2 origin continued dividing (the half-maximal effects was at 0.31 microM).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathalogy, University of Wales College of Medicine, Cardiff, UK.

ABSTRACT
The anticancer agent topotecan is considered to be S-phase specific. This implies that cancer cells that are not actively replicating DNA could resist the effects of the drug. The cycle specificity of topotecan action was investigated in MCF-7 cells, using time-lapse microscopy to link the initial cell cycle position during acute exposures to topotecan with the antiproliferative consequences for individual cells. The bioactive dose range (0.5-10 microM) for 1-h topotecan exposures was defined by rapid drug delivery and topoisomerase I trapping. Topotecan caused pan-cycle induction and activation of p53. Lineage analysis of the time-lapse sequences identified cells initially in S-phase and G2, and defined the time to mitosis for cells originating from G2, S-phase and G1. Topotecan prevented all mitoses from S-phase cells and G1 cells (half-maximal effects at 0.14 microM and 0.96 microM, respectively). No dose of topotecan completely prevented mitosis among G2 cells, and at saturating doses of topotecan about half the cells of G2 origin continued dividing (the half-maximal effects was at 0.31 microM). Overall, topotecan differentially targeted G1-, S- and G2-phase cells, but many G2 cells were resistant to topotecan, presenting a clear route for cell cycle-mediated drug resistance.

Show MeSH
Related in: MedlinePlus