Dual Compartmental Targeting of Cancer

描述（由申请人提供）：该项目的长期目标是最大限度地提高含有分子靶向抗血管生成/抗肿瘤化合物和常规细胞毒性化疗的联合治疗的治疗效果。为了实现这一目标，将测试以下药物的治疗组合：ZD6474，一种新型抗血管生成/抗肿瘤酪氨酸激酶抑制剂，作用于亚微摩尔水平的VEGF受体1 （flt-1）和2 （KDR/flk-1）以及EGF受体；多西他赛，用于乳腺癌治疗的一线化疗药物；以及目前用于结肠癌患者的化疗药物CPT-11。我们将在小鼠原发正常细胞和肿瘤内皮细胞以及人乳腺和结肠肿瘤细胞的体外实验中评估组合的治疗效果，因为这些细胞类型代表了肿瘤的不同区室，可以基于抗血管生成或抗肿瘤方法进行治疗。由于ZD6474和细胞毒性化疗药物都可以根据药物暴露的浓度和/或持续时间引起抗血管生成或抗肿瘤反应，因此最初的研究将集中在体外作用的浓度和时间依赖性上。然后将进行多西紫杉醇和CPT-11的药代动力学研究，以开发基于生理的药代动力学（PBPK）。

DESCRIPTION (provided by applicant): The long-term objective of this project is to maximize the therapeutic benefit of combination therapies containing molecularly targeted antiangiogenic/antitumor compounds and conventional cytotoxic chemotherapy. To accomplish this, therapeutic combinations of the following agents will be tested: ZD6474, a novel antiangiogenic/antitumor tyrosine kinase inhibitor acting on both VEGF receptors 1 (flt-1) and 2 (KDR/flk-1) as well as the EGF receptor at sub micromolar levels; docetaxel, a first line chemotherapeutic agent used in breast cancer treatment; and CPT-11, a current chemotherapeutic for colon cancer patients. Therapeutic efficiency of combinations will be evaluated in mouse primary normal and tumor endothelial cells and human breast and colon tumor cells in vitro, because these cell types represent separate compartments of the tumor for therapeutic targeting based on antiangiogenic or antitumor approaches. Since both ZD6474 and the cytotoxic chemotherapeutic agents can elicit either an antiangiogenic or antitumor response based on the concentration and/or duration of drug exposure, initial studies will focus on the concentration and time-dependence of effects in vitro. Pharmacokinetic studies will then be carried out with docetaxel and CPT-11 for the purpose of development of physiologically-based pharmacokinetic (PBPK) models. PBPK models are the most scientifically valid method for simulation of dose and dose-schedules that will produce in vivo drug concentrations and exposures for maximal therapeutic effect in the vascular endothelial or tumor compartment based on in vitro studies. Dose and dose-schedules will be developed for ZD6474 in combination with CPT-11 or docetaxel that optimize the antiangiogenic or antitumor activity of each component of therapy, and these combinations will be tested against human tumor xenografts in nude mice. The predicted antiangiogenic and antitumor activity of each therapeutic protocol will be evaluated in the tumor xenografts by measuring endothelial and tumor cell proliferation and apoptosis. The pharmacokinetic (PK), pharmacodynamic (PD) and therapeutic information from the proposed studies will be used for designing clinical trials using these drug combinations.