Preclinical pharmacokinetic and pharmacodynamic evaluation of metronomic and conventional temozolomide dosing regimens
Preclinical pharmacokinetic and pharmacodynamic evaluation of metronomic and conventional temozolomide dosing regimens
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DOI：
10.1124/jpet.106.118265
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Gallo, James M.
中科院分区：
文献类型：
--
作者：
Zhou, Qingyu;Guo, Ping;Gallo, James M.
与常规给药（CD）化疗相反，节拍给药（MD）化疗被认为是靶向血管生成和限制宿主毒性的替代策略。虽然这种方法是有前途的，但还没有任何尝试通过整合药代动力学（PK）与药效学（PD）测量来定义最佳节拍给药方案。本研究的目的是比较MD和CD方案后替莫唑胺[TMZ，8-氨基甲酰基-3-甲基偶氮（5，1-d）-1，2，3，5-特拉嗪-4（3 H）-酮]的药代动力学和药效学。在接受18 mg/kg/天TMZ治疗5天或3.23 mg/kg/天TMZ治疗28天的异种移植无胸腺大鼠中进行体内研究。在给药的第一天和最后一天进行PK研究。PD测量包括各种血管生成标志物的基因和蛋白表达、肿瘤大小、肿瘤pH值和间质液压（IFP）。结果表明，MD和CD组的PK参数（总清除率、分布容积和肿瘤/血浆蓄积）非常相似，与TMZ的线性PK特性一致。与溶剂对照治疗相比，两种TMZ治疗方案均导致IFP和肿瘤大小显著降低，证明MD和CD方案的有效性相当。使用实时聚合酶链反应和蛋白质印迹分析，注意到血管内皮生长因子和缺氧诱导因子-1 α的表达水平的一些差异，这表明MD方案可能是上级的CD方案，防止肿瘤进展到促血管生成状态。总之，已经确定了有助于MD TMZ治疗抗肿瘤活性的几个PK/PD因素，并为进一步研究低剂量TMZ方案奠定了基础。
Metronomic dosed ( MD) chemotherapy as opposed to conventional dosed ( CD) chemotherapy is considered an alternate strategy to target angiogenesis and limit host toxicity. Although this approach is promising, there has not been any attempt to define optimal metronomic dosing regimens by integrating pharmacokinetic (PK) with pharmacodynamic (PD) measurements. The aim of this study was to compare the pharmacokinetics and pharmacodynamics of temozolomide [TMZ,8-carbamoyl-3-methylidazo(5,1-d)-1,2,3,5-terrazin-4(3H)-one] after MD and CD regimens. In vivo studies were carried out in xenografted athymic rats treated with either 18 mg/kg/day TMZ for 5 days or 3.23 mg/kg/day TMZ for 28 days. PK studies were performed on the first and last days of dosing. PD measurements consisted of gene and protein expression of various angiogenic markers, tumor size, tumor pH, and interstitial fluid pressure (IFP). The results demonstrated that the PK parameters ( total clearance, volume of distribution, and tumor/plasma accumulation) were quite similar for MD and CD groups, consistent with the linear PK properties of TMZ. Both TMZ treatment schedules caused a significant decrease in IFP and tumor size compared with vehicle control treatment, demonstrating comparable effectiveness of MD and CD regimens. Using real-time polymerase chain reaction and Western blot analyses, some differences were noted in expression levels of vascular endothelial growth factor and hypoxia inducible factor-1 alpha, suggesting that the MD regimen may be superior to the CD regimen by preventing tumors from progressing to a proangiogenic state. In conclusion, several PK/PD factors contributing to the antitumor activity of the MD TMZ therapy have been identified and form a foundation for further investigations of low-dose TMZ regimens.