Dependence of fluorodeoxyuridine-mediated radiosensitization on S phase progression.

Recent evidence casts doubt on the hypotheses that fluoropyrimidine-mediated radiosensitization is related to cytotoxicity or to cell cycle redistribution into the G1/S boundary. We hypothesized that cells that are capable of progressing into S phase in the presence of fluorodeoxyuridine may also be more susceptible to radiation-induced damage. To test this hypothesis, fluorodeoxyuridine (FdUrd)-treated HT29 human colon cancer cells were separated by centrifugal elutriation into four fractions (1-4) containing a range of cells from those at the G1/S boundary (fraction 1) to those which had progressed approximately 11% into S phase (fraction 4). We found that fraction 4 cells showed significantly greater radiosensitization than fraction 1 cells. We also compared the effects of fluorodeoxyuridine on HT29 and SW620 human colon cancer cells. We found that, in contrast with HT29 cells, SW620 cells arrested at the G1/S boundary and were minimally radiosensitized. Finally, we found that an increase in sensitivity was correlated with a decrease in the rate of repair of DNA double-strand and single-strand breaks (assessed by asymmetric field inversion gel electrophoresis and alkaline elution respectively). These findings are consistent with the hypothesis that fluorodeoxyuridine-mediated radiosensitization depends on S phase progression and a decreased ability to repair radiation-induced DNA damage.

[1]  T. Lawrence,et al.  Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects. , 1994, International journal of radiation oncology, biology, physics.

[2]  T. Lawrence,et al.  Induction of resistance to fluorodeoxyuridine cytotoxicity and DNA damage in human tumor cells by expression of Escherichia coli deoxyuridinetriphosphatase. , 1994, Cancer research.

[3]  T. Lawrence,et al.  Influence of cell cycle phase on radiation-induced cytotoxicity and DNA damage in human colon cancer (HT29) and Chinese hamster ovary cells. , 1994, Radiation research.

[4]  T. Lawrence,et al.  Resistance to fluorodeoxyuridine-induced DNA damage and cytotoxicity correlates with an elevation of deoxyuridine triphosphatase activity and failure to accumulate deoxyuridine triphosphate. , 1993, Cancer research.

[5]  T. Lawrence,et al.  The use of biphasic linear ramped pulsed field gel electrophoresis to quantify DNA damage based on fragment size distribution. , 1993, International journal of radiation oncology, biology, physics.

[6]  M. Kessler,et al.  Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  T. Lawrence,et al.  Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: implications for mechanisms of resistance and cytotoxicity. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  T. Lawrence,et al.  The potential superiority of bromodeoxyuridine to iododeoxyuridine as a radiation sensitizer in the treatment of colorectal cancer. , 1992, Cancer research.

[9]  T. Kinsella,et al.  Radiosensitization by fluorodeoxyuridine: effects of thymidylate synthase inhibition and cell synchronization. , 1992, Cancer research.

[10]  T. Lawrence,et al.  The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells. , 1991, International journal of radiation oncology, biology, physics.

[11]  T. Lawrence,et al.  Fluorodeoxyuridine-mediated modulation of iododeoxyuridine incorporation and radiosensitization in human colon cancer cells in vitro and in vivo. , 1991, Cancer research.

[12]  T. Lawrence,et al.  Induction of megabase DNA fragments by 5-fluorodeoxyuridine in human colorectal tumor (HT29) cells. , 1991, Molecular pharmacology.

[13]  T. Lawrence,et al.  Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells. , 1990, International journal of radiation oncology, biology, physics.

[14]  R. Schimke,et al.  Thermal denaturation of DNA for immunochemical staining of incorporated bromodeoxyuridine (BrdUrd): critical factors that affect the amount of fluorescence and the shape of BrdUrd/DNA histogram. , 1989, Cytometry.

[15]  S. Lönn,et al.  Increased levels of DNA lesions induced by leucovorin-5-fluoropyrimidine in human colon adenocarcinoma. , 1988, Cancer research.

[16]  T. Lawrence.  Reduction of doxorubicin cytotoxicity by ouabain: correlation with topoisomerase-induced DNA strand breakage in human and hamster cells. , 1988, Cancer research.

[17]  W. Washtien.  Comparison of 5-fluorouracil metabolism in two human gastrointestinal tumor cell lines. , 1984, Cancer research.

[18]  W. Sadee,et al.  Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. , 1980, Cancer research.

[19]  C B Bagwell,et al.  Nonparametric flow cytometry analysis. , 1979, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[20]  K. Kohn,et al.  Fractionation of DNA from mammalian cells by alkaline elution. , 1976, Biochemistry.

[21]  W. K. Sinclair.  Cyclic X-Ray Responses in Mammalian Cells in Vitro1 , 1968 .

[22]  M. Kessler,et al.  The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy. , 1995, International journal of radiation oncology, biology, physics.

[23]  J. Maybaum,et al.  Fluoropyrimidines as Radiation Sensitizers. , 1993, Seminars in radiation oncology.

[24]  B. Baguley,et al.  A comparison of the effects of aphidicolin and other inhibitors on topoisomerase II-directed cytotoxic drugs. , 1993, Oncology research.

[25]  D. Murray,et al.  Radiosensitization of cultured human colon adenocarcinoma cells by 5-fluorouracil: effects on cell survival, DNA repair, and cell recovery. , 1992, International journal of radiation oncology, biology, physics.

[26]  G. Iliakis,et al.  Measurement of DNA double-strand breaks in CHO cells at various stages of the cell cycle using pulsed field gel electrophoresis: calibration by means of 125I decay. , 1991, International journal of radiation biology.

[27]  L. Tolmach,et al.  Variations in several responses of HeLa cells to x-irradiation during the division cycle. , 1963, Biophysical journal.