Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-methoxyestradiol in prostate cancer models
Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-methoxyestradiol in prostate cancer models
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DOI：
10.1158/0008-5472.can-07-1755
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Amorino, George P.
中科院分区：
文献类型：
--
作者：
Casarez, Eli V.;Dunlap-Brown, Marya E.;Amorino, George P.
2-甲氧基雌二醇（2 ME 2）是一种内源性雌二醇代谢产物，可抑制微管聚合、肿瘤生长和血管生成。由于前列腺癌通常用放射疗法治疗，并且2 ME 2已显示出作为抗人前列腺癌的单一药剂的功效，我们评估了2 ME 2作为前列腺癌模型中的潜在放射增敏剂。在用2 ME 2处理18 h的人PC 3前列腺癌细胞中观察到丝裂原活化蛋白激酶磷酸化的剂量依赖性降低。这种减少与体外放射增敏测定克隆，这些影响被阻断的组成性活性MEK的表达。在后腿中具有皮下PC 3异种移植物的雄性裸鼠用2 ME 2（75 mg/kg）p.o.连续5天，每天2次戈伊照射，剂量为4 μ l。使用动物内斜率分析，在该皮下模型中观察到辐射和2 ME 2之间的统计学显著性超加和效应。还使用PC-3 M原位模型，以生物发光成像作为终点。将稳定表达荧光素酶基因的PC-3 M细胞通过手术植入雄性裸小鼠的前列腺中。小鼠口服2 ME 2（75 mg/kg），4 h后给予放射剂量（3戈伊）。然后用Xenogen系统每周对小鼠进行成像，持续4至5周。在原位模型中也观察到显著的超加性效应。这些数据表明，2 ME 2是一种有效的放射增敏剂对人前列腺癌异种移植物，其机制可能涉及减少丝裂原活化蛋白激酶磷酸化的2 ME 2。
2-Methoxyestradiol (2ME2) is an endogenous estradiol metabolite that inhibits microtubule polymerization, tumor growth, and angiogenesis. Because prostate cancer is often treated with radiotherapy, and 2ME2 has shown efficacy as a single agent against human prostate carcinoma, we evaluated 2ME2 as a potential radiosensitizer in prostate cancer models. A dose-dependent decrease in mitogen-activated protein kinase phosphorylation was observed in human PC3 prostate cancer cells treated with 2ME2 for 18 h. This decrease correlated with in vitro radiosensitization measured by clonogenic assays, and these effects were blocked by the expression of constitutively active MEK. Male nude mice with subcutaneous PC3 xenografts in the hind leg were treated with 2ME2 (75 mg/kg) p.o. for 5 days, and 2 Gy radiation fractions were delivered each day at 4 It after drug treatment. A statistically significant super-additive effect between radiation and 2ME2 was observed in this subcutaneous model, using analysis of within-animal slopes. A PC-3M orthotopic model was also used, with bioluminescence imaging as an end point. PC-3M cells stably expressing the luciferase gene were surgically implanted into the prostates of male nude mice. Mice were given oral doses of 2ME2 (75 mg/kg), with radiation fractions (3 Gy) delivered 4 h later. Mice were then imaged weekly for 4 to 5 weeks with a Xenogen system. A significant super-additive effect was also observed in the orthotopic model. These data show that 2ME2 is an effective radiosensitizing agent against human prostate cancer xenografts, and that the mechanism may involve a decrease in mitogen-activated protein kinase phosphorylation by 2ME2.