Simultaneous alteration of de novo and salvage pathway to the deoxynucleoside thriphosphate pool by (E)-2'-deoxy-(fluoromethylene)cytidine (FMDC) and zidovudine (AZT) results in increased radiosensitivity in vitro.

in Acta Oncologica (2007), 46

Abstract To test whether a thymidine analog zidovudine (=AZT), is able to modify the radiosensitizing effects of (E)-2'-Deoxy-(fluoromethylene)cytidine (FMdC). A human colon cancer cell line Widr was ... [more ▼]

Abstract To test whether a thymidine analog zidovudine (=AZT), is able to modify the radiosensitizing effects of (E)-2'-Deoxy-(fluoromethylene)cytidine (FMdC). A human colon cancer cell line Widr was exposed for 48 hours prior to irradiation to FMdC. Zidovudine was added at various concentrations immediately before irradiation. We measured cell survival and the effect of FMdC, AZT and FMdC + AZT on deoxynucleotide triphosphate pool. FMdC results in a significant increase of radiosensitivity. The enhancement ratios (ER =surviving fraction irradiated cells/surviving fraction drug treated and irradiated cells), obtained by FMdC or AZT alone are significantly increased by the combination of both compounds. Adding FMdC to AZT yields enhancement ratios ranging from 1.25 to 2.26. FMdC reduces dATP significantly, with a corresponding increase of TTP, dCTP and dGTP. This increase of TTP, dCTP and dGTP is abolished with the addition of AZT. Adding AZT to FMdC results in a significant increase of the radiosensitizing effect of FMdC. This combination appears to reduce the reactive enhancement of TTP, dCTP and dGTP induced by FMdC while it does not affect the inhibitory effect on dATP. [less ▲]

Cell-line specific radiosensitizing effect of zalcitabine (DDC)

in Acta Oncologica (1997)

The potential of zalcitabine (ddC) to act as an ionizing radiation response modifier was tested on exponentially growing human cancer cells in vitro. Two human cell lines, WiDr (colon) and MCF-7 (breast ... [more ▼]

The potential of zalcitabine (ddC) to act as an ionizing radiation response modifier was tested on exponentially growing human cancer cells in vitro. Two human cell lines, WiDr (colon) and MCF-7 (breast) were exposed to ddC at 10 p M concentration for various lengths of tide (18, 24, 48 and 72 h). On the WiDr cell line the dual effect of concentration and duration of exposure prior to irradiation was investigated. Experimental endpoints were clonogenicity and viability, as measured by colony formation assay (CFA) and MTT assay respectively. The impact on cell-cycle distribution prior to irradiation was assessed by flow cytometry using a double labeling technique (propidium iodide and bromodeoxyuridine pulse label). A significant reduction in surviving fraction and viability was observed for WiDr-cells irradiated after pre-exposure to 10 pM for 18, 48 and 72 h as compared to corresponding irradiated controls. At lower concentrations (1 and 5 pM), the radiosensitizing effect was only significant after a 72-h exposure (assessed by CFA). For MCF-7, ddC induced a significant modification of the dose response only with 24 and 48 h preincubation. However, the overall effect was less pronounced as compared to WiDr. Cell-cycle analysis showed accumulation in S-phase, 48 and 72 h after treatment with 10 pM ddC in the WiDr cells, with a progressive shift to late S-phase as shown by the biparametric analysis. The degree of radiosensitization is cell-line dependent with the most important sensitization observed on the most <<radioresistant cell line>>, ix., the cell line with the lowest alpha value and highest SF 2 (WiDr). For WiDr, radiosensitization by ddC depends on the duration of exposure and the concentration of the drug. Received 29 February 1996 Accepted 10 December 1996 [less ▲]