Dual Compartmental Targeting of Cancer

癌症的双室靶向

• 批准号: 7343524
• 负责人: DANIEL L GUSTAFSON
• 金额: $ 22.22万
• 依托单位: COLORADO STATE UNIVERSITY
• 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/7343524
• 关键词: Angiogenesis Inhibitors; Antitumor Response; Apoptosis; Blood Vessels; Breast; Breast Cancer Treatment; Cancer Patient; Cell Proliferation; Clinical Trials Design; Colon Carcinoma; Colonic Neoplasms; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; Dependence; Development; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Endothelial Cells; Epidermal Growth Factor Receptor; Human; In Vitro; Lung Neoplasms; Malignant Neoplasms; Measures; Methods; Mus; Nude Mice; Pharmaceutical Preparations; Pharmacodynamics; Protocols documentation; Purpose; Research Personnel; Schedule; Simulate; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Treatment Protocols; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model; ZD-6474; base; cell type; chemotherapeutic agent; colon cancer cell line; cytotoxic; docetaxel; in vivo; models and simulation; neoplastic cell; novel; pharmacokinetic model; programs; response; simulation; therapeutic target; tumor; tumor xenograft

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化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，以亚微摩尔水平作用于 VEGF 受体 1 (flt-1) 和 2 (KDR/flk-1) 以及 EGF 受体；多西紫杉醇，一种用于乳腺癌治疗的一线化疗药物；和 CPT-11，目前用于结肠癌患者的化疗药物。将在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中体外评估组合的治疗效率，因为这些细胞类型代表肿瘤的不同区室，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/或持续时间引发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。然后将使用多西紫杉醇和 CPT-11 进行药代动力学研究，以开发基于生理学的药代动力学 (PBPK) 模型。 PBPK 模型是模拟剂量和剂量方案最科学有效的方法，可根据体外研究产生体内药物浓度和暴露量，以在血管内皮或肿瘤区室中产生最大治疗效果。将开发 ZD6474 与 CPT-11 或多西他赛组合的剂量和剂量方案，以优化治疗中每种成分的抗血管生成或抗肿瘤活性，并且这些组合将针对裸鼠中的人类肿瘤异种移植物进行测试。通过测量内皮细胞和肿瘤细胞的增殖和凋亡，在肿瘤异种移植物中评估每种治疗方案的预测抗血管生成和抗肿瘤活性。拟议研究中的药代动力学 (PK)、药效学 (PD) 和治疗信息将用于设计使用这些药物组合的临床试验。