【作者】 高德轩； 夏庆华； 吕家驹； 张辉；

【Author】 1 Department of Urology,Shandong Provincial Hospital Shandong University,Jinan,People’s Republic of China.Dexuan Gao~1 Qinghua Xia~1 Jiaju Lv~(1*) Hui Zhang~1.

【机构】 山东省立医院泌尿外科；

【摘要】 目的为了进一步探讨丙戊酸(VPA)长期给药抑制人雄激素非依赖性前列腺癌 PC3细胞裸鼠移植瘤生长的效应。方法建立 PC3细胞裸鼠移植瘤模型,治疗组给与含0．4%丙戊酸钠饮用水,而对照组给与纯的饮用水,每隔两天测量肿瘤体积一次,给药时间是4周。取裸鼠移植瘤组织,免疫组化检测 p21WAF/CIP 和 Ki67,Western blot 检测 p21WAF/CIP 和乙酰化 H3(Ac-H3)蛋白的表达, Tunnel 法检测肿瘤细胞的凋亡。结果对照组肿瘤体积大于治疗组,肿瘤生长抑制率为77．27%。免疫组化表明治疗组 p21WAF/CIP 表达强于对照组,而治疗组 Ki67表达弱于对照组。治疗组 p21WAF/CIP 表达明显强于对照组,差异有统计学意义(P＜0．01)。治疗组 Ac-H3表达增加,有统计学意义(P＜0．01)。Tunnel 法检测发现治疗组平均每个视野中凋亡细胞数高于对照组,差异有显著性(P＜0．01)。结论 VPA 长期给药对 PC3细胞移植瘤生长抑制作用明显,是通过抑制细胞增殖,诱导凋亡实现的。更多还原

【Abstract】 Valproic acid (VPA) is an established drug in the long-term therapy of seizure disorders.Recently,VPA has been associated with anticancer activity,an effect thought to be mediated through the inhibition of cellular histone deacetylase 1.Methods:we established PC3 cell line tumor xenografts.There was a treatment arm consisting of a set of animals given 0.4% VPA in their drinking water until tumors reach a size of at least 5 mm in longest dimension.At the end of the 28 day experiment,tumors were harvested,whole blood collected and serum analyzed for VPA,liver function tests (transaminases) and complete blood count.DNA strand breaks were identified by terminal deoxynucleotidyltransferase-mediated UTP end labeling technique using the in situ Cell Death Detection Kit.We investigated the effect of VPA administered chronically on histone acetylation,p21WAF/CIP gene expression by Western blot.Ki67 and p21WAF/CIP were detected by lmmunohistochemistry in tissue of PC3 cell line tumor exongratis.All numerical data were expressed as the average of the values obtained 4- SD.Statistical significance was calculated by the Student’s t test for paired comparisons,when appropriate,by Wilcoxon rank-sum test,or by repeated measures two-way ANOVA with post-hoe testing for comparison of dose treatment effects,where applicable.P ＜0.05 was considered statistically significant.Results:Chronic VPA treatment results in statistically significant reduction of tumor xenograft growth in vivo.Tumor volumes were measured and compared using the Wilcoxon rank-sum test and 2-way ANOVA with post-hoe testing.Animals treated with VPA showed statistically significant reduction in tumor volume compared with controls with 77.27% growth inhibition.Treatment of xenografts with VPA induced significant increase in levels of acetylated histone H3 and p21WAF/CIP compared to the untreated control (P＜0.01).In the VPA treated tumors,apoptotic cell death was markedly increased compared with control tumors (P＜0.01). Ki67 expression in control was stronger than the treated ann (P＜0.01).Conclusion:We conclude that chronic administration of VPA results in significant reduction in PC3 cell line tumor exongraft volume in vivo.These data provide compelling evidence that additional studies are warranted in evaluating the potential use of chronic VPA as a means of altering androgen independent prostate cancer cell growth and progression.更多还原