Mismatch repair proficiency is not required for radioenhancement by gemcitabine.
OBJECTIVE
Mismatch repair (MMR) proficiency has been reported to either increase or decrease radioenhancement by 24-h incubations with gemcitabine. This study aimed to establish the importance of MMR for radioenhancement by gemcitabine after short-exposure, high-dose treatment and long-exposure, low-dose treatment.


METHODS
Survival of MMR-deficient HCT116 and MMR-proficient HCT116 + 3 cells was analyzed by clonogenic assays. Mild, equitoxic gemcitabine treatments (4 h, 0.1 microM vs. 24 h, 6 nM) were combined with gamma-irradiation to determine the radioenhancement with or without recovery. Gemcitabine metabolism and cell-cycle effects were evaluated by high-performance liquid chromatography analysis and bivariate flow cytometry.


RESULTS
Radioenhancement after 4 h of 0.1 microM of gemcitabine was similar in both cell lines, but the radioenhancement after 24 h of 6 nM of gemcitabine was reduced in MMR-proficient cells. No significant differences between both cell lines were observed in the gemcitabine metabolism or cell-cycle effects after these treatments. Gemcitabine radioenhancement after recovery was also lower in MMR-proficient cells than in MMR-deficient cells.


CONCLUSIONS
Mismatch repair proficiency decreases radioenhancement by long incubations of gemcitabine but does not affect radioenhancement by short exposures to a clinically relevant gemcitabine dose. Our data suggest that MMR contributes to the recovery from gemcitabine treatment.
van Bree
Chris
C
Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. c.vanbree@amc.uva.nl
Rodermond
Hans M
HM
de Vos
Judith
J
Haveman
Jaap
J
Franken
Nicolaas A P
NA
D020137:Base Pair Mismatch; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D000093542:Gemcitabine
C081448:MLLT1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; D003841:Deoxycytidine; D004247:DNA; D000093542:Gemcitabine