Significant increase in residual DNA damage as a possible mechanism of radiosensitization by gemcitabine.
OBJECTIVE
To investigate the effect of gemcitabine (dFdC), a promising radiosensitizing nucleoside analog, on the induction and repair of DNA double-strand breaks (dsbs) after ionizing radiation (RT) in a pancreatic tumor cell line.


METHODS
BxPC3 pancreatic tumor cells were treated using different concentrations of gemcitabine with and without subsequent irradiation. DNA dsbs were detected by constant-field gel electrophoresis under neutral conditions.


RESULTS
With the addition of gemcitabine (0.5-1,000 micromol/l for 2 h prior to RT) to RT (0-75 Gy), a considerable and dose-dependent increase of remaining DNA damage after 24 h (5.4-fold for 0.5 micromol/l dFdC, 12.2-fold for 1,000 micromol/l dFdC at 25 Gy) was noted. Enhancement factors were inversely correlated with increasing X-ray dose (7.8-fold for 0.5 micromol/l at 1 Gy decreasing to 1.6-fold at 75 Gy). Conversely, the induction of DNA dsbs was not affected. Gemcitabine alone lead to a slight increase of initial DNA dsbs and only a modest elevation of residual DNA damage.


CONCLUSIONS
These findings strengthen the hypothesis of DNA repair inhibition as a major mechanism of radiosensitization by gemcitabine.
Weiss
Christian
C
Department of Radiation Oncology, Friedrich Alexander University of Erlangen-Nürnberg, Germany.
Grabenbauer
Gerhard G
GG
Sauer
Rolf
R
Distel
Luitpold
L
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000528:radiation effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004586:Electrophoresis; D006801:Humans; D008962:Models, Theoretical; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011879:Radiotherapy Dosage; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D004247:DNA; D000093542:Gemcitabine