INTERACTIONS BETWEEN CYTOTOXIC AND ANTIANGIOGENIC DRUGS

描述：血管生成抑制剂是一组不同的药物， 控制新生血管，这是与肿瘤恶性相关的关键过程。 因此，联合使用细胞毒性(DNA烷化剂)和抗血管生成药物 药物治疗是一种新兴的癌症治疗化疗策略， 因为两个不同的药理靶点可能会受到影响。的目标 这一应用是为了表征药物动力学和药效学。 细胞毒药物相互作用的基础 1，3-二(2-氯乙基)-1-亚硝脲(BCNU)和替莫唑胺((TMZ))和 血管生成抑制剂，TNP-470单独和联合应用 异种移植裸鼠模型。研究计划包括两个具体目标，即 将检验7个假说。药代动力学测量将包括一系列 血浆和肿瘤间质液药浓度，由 基于DNA加合物形成的微透析和药效学评价。 我们将通过一系列的生物学测量来了解 任何药物相互作用的机制基础。生物数据将会 包括血管内皮生长的免疫组织化学测量 血管内皮生长因子(VEGF)及其内皮细胞受体(Flk-1和Flt-1)，因子VIII， 血液流动和肿瘤氧合。将被检验的关键假设 血管生成抑制剂会改变肿瘤的毛细血管通透性 因此，通过血管内皮生长因子介导的细胞毒药物的摄取和毒性 路径。为这一应用开发的异种移植大鼠模型将使用 皮下注射低表达和高表达血管内皮生长因子的胶质瘤细胞 脑内(IC)以确定血管内皮生长因子在药物转运和 细胞毒性。长期目标是确定药理作用 这些细胞毒药物与血管生成抑制剂的相互作用 未来在临床试验中的应用。

DESCRIPTION: Angiogenesis inhibitors are a diverse group of agents that control neovascularization, a critical process related to tumor malignancy. Therefore combination cytotoxic (DNA alkylating agents) and anti-angiogenic drug therapy is an emerging chemotherapeutic strategy for cancer treatment, since two distinct pharmacological targets can be affected. The goals of this application are to characterize the pharmacokinetic and pharmacodynamic basis for interactions between cytotoxic drugs (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide ((TMZ)) an the angiogenesis inhibitor, TNP-470 alone and in combination utilizing a xenograft nude rat model. The research plan includes two specific aims that will test 7 hypotheses. Pharmacokinetic measurements will consist of serial plasma and tumor interstitial fluid drug concentrations, collected by microdialysis and pharmacodynamic assessments based on DNA adduct formation. A series of biological measurements will be obtained to understand the mechanistic basis of any drug interactions. The biological data will consist of immunohistochemical measurements of vascular endothelial growth factor (VEGF) its endothelial cell receptors (flk-1 and flt-1), factor VIII, blood flow, and tumor oxygenation. The key hypothesis that will be tested is that angiogenesis inhibitors will alter tumor capillary permeability and accordingly, uptake and toxicity of cytotoxic drugs by mediation of the VEGF pathway. The xenograft rat model developed for this application will use a low and high VEGF expressing glioma cells injected subcutaneously (SC) and intracerebrally (IC) to determine the role of VEGF in drug transport and cytotoxicity. The long range goal is to determine the pharmacological interactions of these cytotoxic drugs and the angiogenesis inhibitor for future utilization in clinical trials.