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发挥包含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疗法的治疗效益。为此，我们将测试以下药物的联合治疗效果：新型抗血管生成/抗肿瘤酪氨酸激酶抑制剂ZD6474，它同时作用于血管生成因子受体1(Flt-1)和受体2(KDR/Flk-1)以及亚微分子水平的EGF受体；多西紫杉醇，用于乳腺癌治疗的一线化疗药物；以及CPT-11，目前用于结肠癌患者的化疗药物。将在体外评估小鼠原代正常和肿瘤内皮细胞以及人乳腺和结肠肿瘤细胞的治疗效率，因为这些细胞类型代表肿瘤的不同隔室，用于基于抗血管生成或抗肿瘤方法的治疗靶向。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/或持续时间而引起抗血管生成或抗肿瘤反应，初步研究将集中在体外效应的浓度和时间依赖性上。然后将进行多西他赛和CPT-11的药代动力学研究，以开发基于生理的药代动力学(PBPK)。 模特们。PBPK模型是模拟剂量和给药程序的最科学有效的方法，它将在体外研究的基础上，在血管内皮细胞或肿瘤隔室产生最大治疗效果的体内药物浓度和暴露。将开发ZD6474与CPT-11或多西紫杉醇联合使用的剂量和剂量计划，以优化治疗中每个成分的抗血管生成或抗肿瘤活性，并将在裸鼠体内测试这些组合对人肿瘤移植瘤的作用。每种治疗方案预测的抗血管生成和抗肿瘤活性将通过测量内皮细胞和肿瘤细胞的增殖和凋亡来在肿瘤移植瘤中进行评估。来自拟议研究的药代动力学(PK)、药效学(PD)和治疗信息将被用于设计使用这些药物组合的临床试验。

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.