Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines.
The nucleoside analogue 2',2'-difluoro-2'-deoxycytidine (dFdCyd) is a potent radiosensitizer in several solid tumor cell lines. Radiosensitization has correlated with the dFdCyd-mediated decrease in dATP levels and is S-phase specific. Previous studies suggested that a cell line that was unable to progress through S phase after dFdCyd and radiation was not radiosensitized apparently because of the expression of wild-type p53. We have extended these results by using the MCF-7 human breast carcinoma cell line (wild-type p53) and the MCF-7/Adr subline (mutant p53) to determine whether p53 status affected radiosensitization or cell cycle progression after dFdCyd and radiation treatment. Both cell lines were sensitive to nanomolar concentrations of dFdCyd and showed significant radiosensitization, with radiation enhancement ratios of 1.6-1.8 after a 24-h exposure to either the IC(10) or IC(50) for dFdCyd. Nucleotide pool analysis demonstrated a >85% reduction in dATP pools in both cell lines within 8 h after drug addition. Both cell lines accumulated in S phase after a 24-h incubation with dFdCyd. After subsequent irradiation, MCF-7/Adr cells continued to progress through the cell cycle for at least 72 h. MCF-7 cells progressed for at least 24 h, and then exhibited a G(1) block at 48 h after drug and radiation treatment. These results demonstrate that a wild-type p53 cell line can be radiosensitized by dFdCyd, presumably because it was able to deplete dATP levels and progress through the cell cycle for at least 24 h after drug and radiation treatment.
Robinson
B W
BW
Department of Pharmacology, University of Michigan Medical Center, 1310 East Catherine Street, Ann Arbor, MI 48109-0504, USA.
Shewach
D S
DS
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D005838:Genotype; D006801:Humans; D009154:Mutation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D003838:Deoxyadenine Nucleotides; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D000093542:Gemcitabine