Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors
Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors
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DOI：
10.1158/1535-7163.mct-09-0629
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发表时间：
2009-10-01
影响因子：
5.7
通讯作者：
Jung, Mira
中科院分区：
文献类型：
--
作者：
Konsoula, Zacharoula;Cao, Hong;Jung, Mira
结构多样的组蛋白去乙酰化酶抑制剂（HDACI）已经作为化疗剂出现。在这里，我们报告了第一个巯基乙酰胺HDACIs（编码6 MAQH和5 MABMA）用于治疗前列腺癌细胞在体外和体内，并将其血浆药代动力学和组织药效学与肿瘤敏感性。HDACI在体外微粒体稳定性和对前列腺癌和非恶性细胞的生长抑制进行了评估。在腹膜内施用6 MAQH和5 MABMA（0.5和5 mg/Kg）后，使用携带PC 3肿瘤异种移植物的小鼠（n = 10）测定抗肿瘤活性。在无胸腺小鼠中测定了6 MAQH和5 MABMA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HDACIs均显著抑制癌细胞的生长，而对非恶性细胞的作用有限。它们在人、犬和大鼠微粒体中表现出稳定性[6 MAQH的t（1/2）（（min））分别为83、72和66，5 MABMA分别为68、43和70]。两种HDACI（0.5mg/Kg）均导致肿瘤消退[P < 0.01），其持续至少60天。体内数据显示有利的血浆药代动力学，6 MAQH的曲线下面积为4.97 +/- 0.6 μ mol/L x h，5 MABMA的曲线下面积为4.23 +/- 0.43 μ mol/L x h。6 MAQH和5 MABMA的清除率分别为4.05 +/- 0.15和4.87 +/- 0.2 L/h，而半衰期分别为2.2 +/- 0.33和1.98 +/- 0.21 h。两种HDACIs在30分钟内显著增强组织中组蛋白H4的乙酰化，包括脑、肝和脾。总之，这些结果为进一步研究这些巯基乙酰胺HDACIs作为强效抗癌剂提供了依据。[Mol Cancer Ther 2009;8（10）：2844-51]
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 mu mol/L x h for 6MAQH and 4.23 +/- 0.43 mu mol/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. [Mol Cancer Ther 2009;8(10):2844-51]