Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines.
OBJECTIVE
To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells.


METHODS
Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel, 5-fluorouracil (5-FU), methotrexate (MTX), cytarabine (ara-C), and dFdC was measured by a proliferation assay. Radiosensitivity and radioenhancement by dFdC of this cell panel and the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000 were determined by clonogenic assay. Bivariate flowcytometry was performed to study cell cycle changes.


RESULTS
In the SWg, a complete deoxycytidine kinase (dCK) deficiency was found on mRNA and protein level. This was accompanied by a 10-fold decrease in dCK activity which resulted in the >1000-fold resistance to dFdC. Sensitivity to other anti-tumor drugs was not altered, except for ara-C (>100-fold resistance). Radiosensitivity was not altered in the dFdC-resistant cell lines SWg and AG6000. High concentrations (50-100 microM dFdC) induced radioenhancement in the dFdC-resistant cell lines similar to the radioenhancement obtained at lower concentrations (10 nM dFdC) in the parental lines. An early S-phase arrest was found in all cell lines after dFdC treatment where radioenhancement was achieved.


CONCLUSIONS
In the dFdC-resistant lung tumor cell line SWg, the deficiency in dCK is related to the resistance to dFdC and ara-C. No cross-resistance was observed to other anti-tumor drugs used for the treatment in lung cancer. Sensitivity to ionizing radiation was not altered in two different dFdC-resistant cell lines. Resistance to dFdC does not eliminate the ability of dFdC to sensitize cells to radiation.
Academic Medical Center, Department of Radiotherapy, University of Amsterdam, Room F0-205, PO Box 22700, 1100 DE Amsterdam, The Netherlands. c.vanbree@amc.uva.nl
Chris
C
van Bree
Natasja
N
Castro Kreder
Willem J P
WJ
Loves
Nicolaas A P
NA
Franken
Godefridus J
GJ
Peters
Jaap
J
Haveman
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000032:analysis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine