  Alteration of radiation response in vitro by simultaneous modulation of the de novo and salvage pathways to deoxynucleoside triphosphate pool by (E)-2′-Deoxy-(Fluoromethylene)cytidine and thymidine analogsCoucke, Philippe  ; ; et alin International Journal of Radiation, Oncology, Biology, Physics (1997), 39(2 (supp1)), 257 Detailed reference viewed: 4 (1 ULg) Antitumor and radiosensitizing effects of (E)-2'-Deoxy-2'-(Fluoromethylene) cytidine, a novel inhibior of ribonucleotide diphosphate reductase on human colon carcinoma xenografts in nude mice.; ; et al in Cancer Research (1997), 57 Antitumor and radiosensitizing effects of (E).2'-deoxy.2'-(fluromethyl ene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. xenografts and liver ... [more ▼] Antitumor and radiosensitizing effects of (E).2'-deoxy.2'-(fluromethyl ene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. xenografts and liver metastases of a human colon carcinoma. FMdC given once daily or twice weekly has a dose-dependent antitumor effect. The maximum tolerated dose In the mice was reached with 10 mgi'kg applied daily over 12 days. Twice weekly administration of FMdC reduced its toxicity but lowered the antitumor effect. Treatment of preestablished liver micrometastases obtained via intrasplenic injection of tumor cells, with 5 or 10 mgfkg FMdC, signifi candy prolonged the survival of the mice as compared to controls (P < 0.025 and P < 0.001, respectively). Ten mg/kg resulted in longer survival than S mg/kg FMdC (P < 0.05). Radiotherapy alone of s.c. xenografts (10 fractions over 12 days) yielded the radiation dose required to produce local tumor control in 50% of the treated mice (TCD@O)of 43.0 Gy. When combined with FMdC, TCDsawas reduced to 22.5 and 19.0 Gy at doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation, respec tively. The corresponding enhancement ratios were 1.91 and 2.43, respec lively. FMdC produced moderate and reversible myelosuppression. When 5 mg/kg FMdC was combined with irradiation, there was no increased skin or hematological toxicity as compared to radiotherapy or FMdC alone. At the 10 mg/kg level, however, lower leukocyte counts were observed. These results show that FMdC appears to be a potent anticancer drug and radiosensitizer [less ▲] Detailed reference viewed: 7 (1 ULg)Cell-line specific radiosensitizing effect of zalcitabine (DDC)Coucke, Philippe ; ; et alin 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 ▲] Detailed reference viewed: 30 (1 ULg) |
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