Radiosensitizing potential of gemcitabine (2',2'-difluoro-2'-deoxycytidine) within the cell cycle in vitro
| Autor: | Michael Wannenmacher, D. Latz, Katharina Fleckenstein, Johannes Blatter, M.J. Eble, Klaus J. Weber |
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| Rok vydání: | 1998 |
| Předmět: |
Cancer Research
Radiation-Sensitizing Agents Cell Survival Cell Radiation Dosage Deoxycytidine Cell Line S Phase chemistry.chemical_compound Cricetulus Radioresistance Cricetinae medicine Tumor Cells Cultured Animals Humans Radiology Nuclear Medicine and imaging Radiosensitivity Clonogenic assay Radiation Dose-Response Relationship Drug business.industry Cell Cycle Cell cycle Combined Modality Therapy Gemcitabine medicine.anatomical_structure Oncology chemistry Cell culture Immunology Cancer research business medicine.drug |
| Zdroj: | International journal of radiation oncology, biology, physics. 41(4) |
| ISSN: | 0360-3016 |
| Popis: | Purpose: Gemcitabine (2′,2′-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle–specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells. Methods and Materials: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also carried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle–specific enhancement ratios (ER) were calculated from the survival curve parameters. Results: Effectiveness of combined treatment of log-phase cells was greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)]. Conclusions: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been taken to overcome S-phase radioresistance, such as hyperthermia or densely ionizing radiation, and combined treatments with dFdCyd could prove of value to complement such efforts. |
| Databáze: | OpenAIRE |
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