Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines.
Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines.
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发表时间：
2001-08
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通讯作者：
B. Robinson;D. Shewach
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作者：
B. Robinson;D. Shewach
核苷类似物2',2'-二氟-2'-脱氧胞苷（dFdCyd）在几种实体肿瘤细胞系中是一种有效的放射增敏剂。放射致敏与dfdcyd介导的dATP水平下降相关，并且是s期特异性的。先前的研究表明，由于野生型p53的表达，dFdCyd和放疗后不能进入S期的细胞系没有明显的放射致敏性。我们利用MCF-7人乳腺癌细胞系（野生型p53）和MCF-7/Adr亚系（突变型p53）扩展了这些结果，以确定p53状态是否影响dFdCyd和放射治疗后的放射致敏或细胞周期进展。两种细胞系都对纳米摩尔浓度的dFdCyd敏感，并表现出显著的放射增敏，暴露于dFdCyd的IC（10）或IC(50) 24小时后，辐射增强比为1.6-1.8。核苷酸池分析显示，在药物添加后8小时内，两种细胞系的dATP池减少了约85%。用dFdCyd孵育24小时后，两种细胞系均进入S期。在随后的照射后，MCF-7/Adr细胞在细胞周期中持续进展至少72小时。MCF-7细胞进展至少24小时，然后在药物和放射治疗后48小时出现G(1)阻滞。这些结果表明，野生型p53细胞系可以被dFdCyd放射致敏，可能是因为它能够在药物和放射治疗后消耗dATP水平并在细胞周期中进展至少24小时。
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.