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Fluorodeoxyuridine-mediated cytotoxicity and radiosensitization require S phase progression
T S Lawrence1, M A Davis, H Y Tang
1Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109, USA.
International Journal of Radiation Biology
|September 1, 1996
Summary
Fluorodeoxyuridine (FdUrd) radiosensitizes colon cancer cells not just by cell cycle redistribution, but by promoting S phase progression on damaged DNA. Aphidicolin blocks these radiosensitizing effects, indicating S phase progression is crucial.
Area of Science:
- Oncology
- Cancer Biology
- Radiotherapy
Background:
- The mechanism of fluoropyrimidine-induced radiosensitization is not fully understood.
- Cell cycle redistribution is a proposed mechanism for fluoropyrimidine radiosensitization.
Purpose of the Study:
- To investigate whether cell cycle redistribution or S phase progression is responsible for fluorodeoxyuridine (FdUrd)-mediated radiosensitization in HT29 colon cancer cells.
Main Methods:
- HT29 colon cancer cells were treated with FdUrd and sorted into mid-S phase.
- Cells were irradiated to assess radiosensitization.
- Aphidicolin, a DNA polymerase alpha inhibitor, was used to block S phase progression.
Main Results:
- FdUrd-treated mid-S phase cells showed significant radiosensitization, contradicting the cell cycle redistribution hypothesis.
- Aphidicolin treatment blocked the radiosensitizing and cytotoxic effects of FdUrd.
- Cells at the G1/S boundary showed minimal sensitization to FdUrd.
Conclusions:
- FdUrd-mediated radiosensitization is not solely due to cell cycle redistribution.
- S phase progression on a damaged DNA template is a critical factor in both FdUrd-induced radiosensitization and cytotoxicity.