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See detailReproducibility of measurements of potential doubling time of tumour cells in the multicentre National Cancer Institute protocol
COUCKE, Philippe ULg; Paschoud, N; Pavy, J-J et al

in British Journal of Cancer (1999)

We compared the flow cytometric measurement and analysis of the potential doubling time ( Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose ... [more ▼]

We compared the flow cytometric measurement and analysis of the potential doubling time ( Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose was to understand and minimize the variation within the measurement. A total of 102 specimens were selected at random from patients entered into the trial. Samples were prepared, stained, run and analysed in each centre and a single set of data analysed by all three centres. Analysis of the disc data set revealed that the measurement of labelling index (LI) was robust and reproducible. The estimation of duration of S-phase ( Ts) was subject to errors of profile interpretation, particularly DNA ploidy status, and analysis. The LI dominated the variation in Tpot such that the level of final agreement, after removal of outliers and ploidy agreement, reached correlation coefficients of 0.9. The sample data showed poor agreement within each of the components of the measurement. There was some improvement when ploidy was in agreement, but correlation coefficients failed to exceed values of 0.5 for Tpot. The data suggest that observer-associated analysis of Ts and tissue processing and tumour heterogeneity were the major causes of variability in the Tpot measurement. The first two aspects can be standardized and minimized, but heterogeneity will remain a problem with biopsy techniques. [less ▲]

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See detailThe ribonucleoside diphosphate reductase inhibitor (E)-2'-Deoxy-(fluoromethylene) cytidine, acts as a cytotoxic radiosensitizer on human cancer cell lines in vitro.
Coucke, Philippe ULg; Decosterd, L-A; Li, Y-X et al

in Cancer Research (1999), 59

ABSTRACT (E)-2*-Deoxy-(fluoromethylene)cytidine (FMdC) is known as an inhibitor of ribonucleoside diphosphate reductase, a key enzyme in the de novo pathway of DNA synthesis. FMdC was tested as a modifier ... [more ▼]

ABSTRACT (E)-2*-Deoxy-(fluoromethylene)cytidine (FMdC) is known as an inhibitor of ribonucleoside diphosphate reductase, a key enzyme in the de novo pathway of DNA synthesis. FMdC was tested as a modifier of radiation response in vitro on a human colon carcinoma cell line (WiDr), and the observed radiosensitization was confirmed on two human cervix cancer cell lines (C33-A and SiHa). Using the clonogenic assay, the effect ratio (ER) at a clinically relevant dose level of 2 Gy was 2.10 (50 nM FMdC), 1.70 (30 nM FMdC), and 1.71 (40 nM FMdC) for the three cell lines WiDr, C33-A, and SiHa, respectively. A more detailed analysis of the importance of timing and concentration of FMdC was done on the WiDr cell line alone, yielding an increased ER(2Gy) with increasing concentration and duration of exposure to the drug, ranging from 1.0 (6 h) to 1.8 (72 h) at 30 nM FMdC and from 1.2 (6 h) to 3.5 (24 h) at 300 nM. We investigated the effect of FMdC on the cellular deoxynucleotide triphosphate pool in WiDr cells and demonstrated a marked depletion of dATP and a significant rise of TTP levels. Cell cycle analysis showed early S-phase accumulation induced by FMdC alone, G2-M block induced by irradiation alone, and an increased accumulation of cells in G2-M if both modalities are used. Our data suggest that FMdC is a radiation response modifier in vitro on different cancer cell lines. The observed radiosensitization may in part be explained by alteration of the deoxynucleotide triphosphate pool, which is consistent with the effect of FMdC on ribonucleoside diphosphate reductase. [less ▲]

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See detailReproducibility of measurements of potential doubling time of tumor cells in the multicenter NCI protocol T92-0045
Wilson, G-D; Paschoud, N; Pavy, J-J et al

in British Journal of Cancer (1999), 79(2), 323-332

Summary We compared the flow cytometric measurement and analysis of the potential doubling time ( Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary ... [more ▼]

Summary We compared the flow cytometric measurement and analysis of the potential doubling time ( Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose was to understand and minimize the variation within the measurement. A total of 102 specimens were selected at random from patients entered into the trial. Samples were prepared, stained, run and analysed in each centre and a single set of data analysed by all three centres. Analysis of the disc data set revealed that the measurement of labelling index (LI) was robust and reproducible. The estimation of duration of S-phase ( Ts) was subject to errors of profile interpretation, particularly DNA ploidy status, and analysis. The LI dominated the variation in Tpot such that the level of final agreement, after removal of outliers and ploidy agreement, reached correlation coefficients of 0.9. The sample data showed poor agreement within each of the components of the measurement. There was some improvement when ploidy was in agreement, but correlation coefficients failed to exceed values of 0.5 for Tpot. The data suggest that observer-associated analysis of Ts and tissue processing and tumour heterogeneity were the major causes of variability in the Tpot measurement. The first two aspects can be standardized and minimized, but heterogeneity will remain a problem with biopsy techniques. [less ▲]

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See detailPotentiation of cytotoxicity and radiosensitization of (E)-2'-deoxy-2' (fluoromethylene) cytidine by pentoxifylline in vitro.
LI, Y-X; Sun, L-Q; Paschoud, N et al

in International Journal of Cancer = Journal International du Cancer (1999), 80

(E)-28-deoxy-28-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide-diphosphate reductase, has been shown to have anti-tumor activity against solid tumors and sensitize tumor cells to ... [more ▼]

(E)-28-deoxy-28-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide-diphosphate reductase, has been shown to have anti-tumor activity against solid tumors and sensitize tumor cells to ionizing radiation. Pentoxifylline (PTX) can potentiate the cell killing induced by DNAdamaging agents through abrogation of DNA-damagedependent G2 checkpoint. We investigated the cytotoxic, radiosensitizing and cell-cycle effects of FMdC and PTX in a human colon-cancer cell line WiDr. PTX at 0.25–1.0 mM enhanced the cytotoxicity of FMdC and lowered the IC50 of FMdC from 79 6 0.1 to 31.2 6 2.1 nM, as determined by MTT assay. Using clonogenic assay, pre-irradiation exposure of exponentially growing WiDr cells to 30 nM FMdC for 48 hr or post-irradiation to 0.5 to 1.0 mM PTX alone resulted in an increase in radiation-induced cytotoxicity. Moreover, there was a significant change of the radiosensitization if both drugs were combined as compared with the effect of either drug alone. Cell-cycle analysis showed that treatment with nanomolar FMdC resulted in S-phase accumulation and that such an S-phase arrest can be abrogated by PTX. Treatment with FMdC prior to radiation increased post-irradiation-induced G2 arrest, and such G2 accumulation was also abrogated by PTX. These results suggest that pharmacological abrogation of S and G2 checkpoints by PTX may provide an effective strategy for enhancing the cytotoxic and radiosensitizing effects of FMdC. Int. J. Cancer 80:155–160, 1999. [less ▲]

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See detailEffect of pentoxifylline on radiation-induced G2-phase delay and radiosensitivity of human colon and cervical cancer cells.
Li, Y-X; Weber-Johnson, K; Sun, L-Q et al

in Radiation Research (1998), 149(4),

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See detailCytotoxic interactions of 5-fluorouracil and nucleoside analogues in vitro
Li, Y-X; COUCKE, Philippe ULg; Paschoud, N et al

in Anticancer Research (1997), 17(1A), 21-27

The cytotoxic interaction of combined 5-fluorouracil (5-FU) with different nucleoside analogues was investigated in vitro on a colon (WiDr) and a breast (MCF-7) cancer cell line. Azidothymidine (AZT), 3 ... [more ▼]

The cytotoxic interaction of combined 5-fluorouracil (5-FU) with different nucleoside analogues was investigated in vitro on a colon (WiDr) and a breast (MCF-7) cancer cell line. Azidothymidine (AZT), 3'-deoxy-2', 3'-didehydrothymidine (D4T), 5-iododeoxyuridine (IdUrd) and 2',3'-dideoxycytidine (DDC) were tested at different concentrations (5-600 microM) as modulators of 5-FU. The experimental endpoints were cellular viability and cell cycle distribution. The combination of 5-FU and AZT or D4T yielded supra-additive cytotoxic effects in both cell lines at all concentrations. On WiDr, IdUrd at high concentrations of 50 and 100 microM showed a supra-additive effect whereas at low concentrations (5, 10 and 20 microM) the effect was antagonistic. 5-FU combined with IdUrd produced a synergistic effect on MCF-7 cells at all concentrations. DDC antagonised the toxic effect of 5-FU on the WiDr cell line. In WiDr cells, a significant increase in the overall S-phase was observed 48 and 72 hours after exposure to D4T, AZT and DDC at the low concentration of 10 microM. On the contrary, this accumulation in S-phase was not present in MCF-7 cells. The combined effect of 5-FU and nucleoside analogues in vitro is dependent on the type and concentration of nucleosides and the cell-line tested. AZT, D4T and IdUrd are more likely to be subjected to more intensive in vitro and in vivo research as far as modulation of 5-FU toxicity is concerned. [less ▲]

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See detailModulation of the radiosensitizing effect of (E)-24-deoxy-(fluoromethylene)cytidine (FMdC)by thymide analogues AZT, D4T and idUrd.
COUCKE, Philippe ULg; Cottin, E; Li, Y-X et al

in Radiotherapy & Oncology (1997), 43(supp 2), 13

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See detailNew ribonucleotide reductase inhibitor, (E)-2′-deoxy-(fluromethylene) cytidine, acts as a radiosensitizer on human colon and cervix cancer cell lines
Coucke, Philippe ULg; LI, XY; Cottin, E et al

in Radiotherapy & Oncology (1996), 40(Supplément 1), 135

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See detailT92-0045: Interlaboratory quality control on Tpot measurements
Coucke, Philippe ULg; Beer, K.; Bernier, J. et al

in International Journal of Radiation, Oncology, Biology, Physics (1996), 36(1(supp1)), 384

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See detailLa cinétique cellulaire tumorale: aspects cliniques «à la recherche du temps perdu»
Coucke, Philippe ULg; Paschoud, N

in Bulletin du Cancer. Radiothérapie : Journal de la Société Française du Cancer : Organe de la Société Française de Radiothérapie Oncologique (1993), 80(4), 431-437

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