Dual Compartmental Targeting of Cancer

癌症的双室靶向

• 批准号: 6998954
• 负责人: DANIEL L GUSTAFSON
• 金额: $ 23.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998954
• 关键词: angiogenesis inhibitors; antineoplastics; athymic mouse; bioassay; cell line; cis platinum compound; clinical research; combination chemotherapy; dosage; drug screening /evaluation; epidermal growth factor; growth factor receptors; human genetic material tag; kinase inhibitor; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; neoplastic growth; paclitaxel; pharmacokinetics; vascular endothelial growth factors; xenotransplantation

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.

描述（由申请人提供）：该项目的长期目标是最大程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学疗法的组合疗法的治疗益处。为此，将测试以下药物的治疗组合：ZD6474，一种新型的抗血管生成/抗肿瘤酪氨酸激酶抑制剂，作用于VEGF受体1（FLT-1）和2（KDR/FLK-1）的抗EGF受体，以及在亚微摩尔水平下的EGF受体；多西他赛，一种用于乳腺癌治疗的第一线化学治疗剂；和CPT-11，是结肠癌患者的当前化学治疗。组合的治疗效率将在小鼠原发性正常和肿瘤内皮细胞以及人类乳腺癌和结肠肿瘤细胞的体外评估，因为这些细胞类型代表了基于抗血管生成或抗肿瘤方法的治疗靶向的肿瘤的单独隔室。由于ZD6474和细胞毒性化学治疗剂均可基于药物暴露的浓度和/或持续时间引起抗血管生成或抗肿瘤反应，因此初步研究将集中于体外效应的浓度和时间依赖性。然后，将使用多西他赛和CPT-11进行药代动力学研究，以开发基于生理的药代动力学（PBPK） 型号。 PBPK模型是模拟剂量和剂量 - 囊肿的最科学有效的方法，这些方法将在基于体外​​研究的血管内皮或肿瘤室中产生体内药物浓度和暴露于最大治疗作用。将为ZD6474与CPT-11或多西他赛的剂量和剂量 - 细节开发，以优化治疗的每个成分的抗血管生成或抗肿瘤活性，这些组合将针对裸鼠中的人肿瘤异种移植物进行测试。每种治疗方案的抗血管生成和抗肿瘤活性将通过测量内皮和肿瘤细胞增殖和凋亡评估在肿瘤异种移植物中。拟议研究的药代动力学（PK），药效学（PD）和治疗信息将用于使用这些药物组合设计临床试验。