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.
Davis
M A
MA
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109-0582, USA.
Tang
H Y
HY
Maybaum
J
J
Lawrence
T S
TS
D002469:Cell Separation; D002470:Cell Survival / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000473:pathology; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005467:Floxuridine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D011838:Radiation-Sensitizing Agents; D016196:S Phase / Q000187:drug effects* / Q000528:radiation effects; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D011838:Radiation-Sensitizing Agents; D005467:Floxuridine; D013940:Thymidylate Synthase