Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.
Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.
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DOI：
10.1186/1476-4598-4-22
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发表时间：
2005-07-07
期刊：
影响因子：
37.3
通讯作者：
Duenas-Gonzalez A
中科院分区：
文献类型：
--
作者：
Chavez-Blanco A;Segura-Pacheco B;Perez-Cardenas E;Taja-Chayeb L;Cetina L;Candelaria M;Cantu D;Gonzalez-Fierro A;Garcia-Lopez P;Zambrano P;Perez-Plasencia C;Cabrera G;Trejo-Becerril C;Angeles E;Duenas-Gonzalez A
癌症的发生与组蛋白脱乙酰酶(HDAC)活性异常等表观遗传学改变有关。最近报道，丙戊酸是组蛋白脱乙酰酶的有效抑制剂，因此可以诱导肿瘤细胞分化、凋亡或生长停滞。12例新诊断的宫颈癌患者在肿瘤活检和采血后给予丙戊酸镁治疗，剂量分别为20 mg/kg、30 mg/kg和40 mg/kg，连续5天。在第6天，重复肿瘤和血液样本，研究方案结束。用Western印迹法检测H3和H4组蛋白的乙酰化程度，用HDAC比色法检测肿瘤细胞的HDAC活性。达到稳态后第6天测定丙戊酸的血药浓度。在研究结束时评估治疗的毒性。所有患者均完成研究用药。所有患者的平均日剂量为1,890毫克。20 mg/kg、30 mg/kg和40 mg/kg剂量的相应平均值分别为1245、2000和2425 mg。9例患者意识状态为2级抑郁。对10名患者进行了H3和H4乙酰化和HDAC活性评估。治疗后，我们分别在9例和7例患者的肿瘤中观察到H3和H4的高乙酰化，而6例患者显示出这两种组蛋白的高乙酰化。丙戊酸的血药浓度范围为73.6~170.49μg/mL。8例患者(80%)肿瘤脱乙酰酶活性降低，2例患者无变化或轻度升高。治疗前后HDAC活性差异有统计学意义(平均值分别为0.36vs.0.21，双尾t检验p<；0.0264)。H3、H4肿瘤高乙酰化与血清丙戊酸水平无相关性。丙戊酸镁剂量在20至40 mg/kg之间时，可抑制肿瘤组织中的脱乙酰酶活性和高乙酰化组蛋白。
The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid. Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
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影响因子：
6.4
作者：
Castro-Galache, MD;Ferragut, JA;Saceda, M
通讯作者：
Saceda, M
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
64.8
作者：
Nan, XS;Ng, HH;Bird, A
通讯作者：
Bird, A
影响因子：
2.5
作者：
JOLLEY, ME
通讯作者：
JOLLEY, ME
影响因子：
11.4
作者：
Krämer, OH;Zhu, P;Göttlicher, M
通讯作者：
Göttlicher, M