FLUORODEOXYURIDINE-INDUCED RADIOSENSITIZATION AND INHIBITION OF DNA DOUBLE STRAND BREAK REPAIR IN HUMAN COLON CANCER-CELLS

被引:80
作者
BRUSO, CE
SHEWACH, DS
LAWRENCE, TS
机构
[1] UNIV MICHIGAN,MED CTR,DEPT RADIAT ONCOL,1331 E ANN ST,ANN ARBOR,MI 48109
[2] UNIV MICHIGAN,MED CTR,DEPT PHARMACOL,ANN ARBOR,MI 48109
来源
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS | 1990年 / 19卷 / 06期
关键词
COLORECTAL CARCINOMA; 5-FLUORODEOXYURIDINE; FDURD; FUDR; RADIATION; DNA DAMAGE; THYMIDYLATE SYNTHASE;
D O I
10.1016/0360-3016(90)90352-K
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The halogenated pyrimidine fluorodeoxyuridine (FdUrd), has been used in combination with radiation for the treatment of human neoplasms. In an attempt to improve the clinical use of this combination. FdUrd-radiation interactions were studied in vitro using human HT29 colon cancer cells. It was found that FeUrd produced radiosensitization at clinically achievable (1-100 nM) concentrations. Sensitization depended critically on the timing of exposure. When cells were irradiated after a 12-hr exposure to 100 nM FdUrd, marked sensitization was produced (mean inactivation dose (MID) = 2.01 +/- 0.01, compared to control of 4.35 +/- 0.16, p < .01). No radiosensitization occurred when cells were irradiated 4 hr prior to incubation (MID = 3.95 +/- 0.05, p > 0.4). Radiosensitization appeared to result from an inhibition of thymidylate synthase since concentrations of FdUrd which produced radiosensitization depleted intracellular TTP pools blocked the incorporation of deoxyuridine into DNA. Furthermore, radiosensitization was completely inhibited by co-incubation with thymidine. FdUrd also decreased the repair, but not the formation, of radiation-induced DNA double strand breaks (DSB's). These data are consistent with the hypothesis that FdUrd produces radiosensitization by depleting thymidine pools which leads to a decreased rate of DNA DSB repair. Furthermore, they suggest that in clinical trials FdUrd should be infused at least 8 hr before irradiation.
引用
收藏
页码:1411 / 1417
页数:7
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