Division of Radiation Biology, Department of Radiation Medicine, The Research Building, Room E-211, Georgetown University School of Medicine, Box 571482, 3970 Reservoir Road, Northwest, Washington, DC 20057-1482, USA.
Mol Cancer Ther. 2009 Oct;8(10):2844-51. doi: 10.1158/1535-7163.MCT-09-0629. Epub 2009 Sep 29.
Structurally diverse histone deacetylase inhibitors (HDACI) have emerged as chemotherapeutic agents. Here, we report the first mercaptoacetamide HDACIs (coded 6MAQH and 5MABMA) for use in treatment against prostate cancer cells in vitro and in vivo and correlate their plasma pharmacokinetics and tissue-pharmacodynamics with tumor sensitivity. HDACIs were assessed for in vitro microsomal stability and growth inhibition against prostate cancer and nonmalignant cells. Antitumor activity was determined following i.p. administration of 6MAQH and 5MABMA (0.5 and 5 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). The plasma pharmacokinetics of 6MAQH and 5MABMA and their effects on the acetylation of histone H4 in tissues were determined in athymic mice. Both HDACIs significantly inhibited the growth of cancer cells while exerting limited effect on nonmalignant cells. They exhibited stability in human, dog, and rat microsomes [t(1/2 (min)) = 83, 72, and 66 for 6MAQH and 68, 43, and 70 for 5MABMA, respectively]. Both HDACIs (0.5 mg/Kg) led to tumor regression (P < 0.01), which was sustained for at least 60 days. In vivo data show favorable plasma pharmacokinetics with the area under the curve of 4.97 +/- 0.6 micromol/L x h for 6MAQH and 4.23 +/- 0.43 micromol/L x h for 5MABMA. The clearance rates for 6MAQH and 5MABMA were 4.05 +/- 0.15 and 4.87 +/- 0.2 L/h, whereas the half-lives were 2.2 +/- 0.33 and 1.98 +/- 0.21 h, respectively. Both HDACIs markedly enhanced the acetylation of histone H4 within 30 minutes in tissues, including the brain, liver, and spleen. Taken together, the results provide a rationale for further investigation of these mercaptoacetamide HDACIs as potent anticancer agents.
结构多样的组蛋白去乙酰化酶抑制剂（HDACI）已成为化疗药物。在这里，我们报告了第一个用于治疗前列腺癌细胞的巯基乙酰胺 HDACI（编码为 6MAQH 和 5MABMA），并在体外和体内将其血浆药代动力学和组织药效动力学与肿瘤敏感性相关联。评估了 HDACI 对前列腺癌和非恶性细胞的体外微粒体稳定性和生长抑制作用。使用携带 PC3 肿瘤异种移植物的小鼠（n = 10），通过腹腔注射 6MAQH 和 5MABMA（0.5 和 5 mg/kg）来确定抗肿瘤活性。在裸鼠中测定了 6MAQH 和 5MABMA 的血浆药代动力学及其对组织中组蛋白 H4 乙酰化的影响。两种 HDACI 均显著抑制癌细胞生长，而对非恶性细胞的作用有限。它们在人、狗和大鼠微粒体中表现出稳定性[6MAQH 的半衰期（t1/2（min））为 83、72 和 66，5MABMA 为 68、43 和 70]。两种 HDACI（0.5 mg/kg）均导致肿瘤消退（P < 0.01），至少持续 60 天。体内数据显示，6MAQH 的曲线下面积为 4.97 +/- 0.6 微摩尔/L x h，5MABMA 的曲线下面积为 4.23 +/- 0.43 微摩尔/L x h，具有良好的血浆药代动力学。6MAQH 和 5MABMA 的清除率分别为 4.05 +/- 0.15 和 4.87 +/- 0.2 L/h，半衰期分别为 2.2 +/- 0.33 和 1.98 +/- 0.21 h。两种 HDACI 均在 30 分钟内在组织中显著增强组蛋白 H4 的乙酰化，包括大脑、肝脏和脾脏。综上所述，这些结果为进一步研究这些巯基乙酰胺 HDACI 作为有效的抗癌剂提供了依据。
