Interactions Between Cytotoxic and Antiangiogenic Drugs

细胞毒性药物和抗血管生成药物之间的相互作用

• 批准号: 8034052
• 负责人: James M. Gallo
• 金额: $ 22.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034052
• 关键词: Address; Affect; Alkylating Agents; Angiogenesis Inhibitors; Angiogenic Factor; Behavior; Blood Vessels; Brain Neoplasms; Cell surface; Characteristics; Clinic; Clinical Research; Clinical Trials; Complex; Cytotoxic agent; Data; Databases; Development; Drug Combinations; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug resistance; Effectiveness; Ensure; Epidermal Growth Factor Receptor; Foundations; Gene Expression; Gene Proteins; Glioma; Goals; Growth; Hybrids; Investigation; Lead; Measurement; Measures; Mediating; Modeling; Molecular; Monitor; Mus; Nature; Neoplasms in Vascular Tissue; Outcome; PDGFRB gene; PTEN gene; Patients; Pharmaceutical Preparations; Pharmacodynamics; Process; Property; Regimen; Research; Resistance; Resistance profile; Series; Solid Neoplasm; Translating; Treatment outcome; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; angiogenesis; base; cytotoxic; design; improved; in vivo; inhibitor/antagonist; novel; pharmacodynamic model; pre-clinical; prospectuses; protein expression; resistance mechanism; response; subcutaneous; temozolomide; tumor

DESCRIPTION (provided by applicant): The growth and invasiveness of solid tumors is highly dependent on angiogenesis or the processes forming new tumor blood vessels. Accordingly the development of antiangiogenic drugs is of considerable importance, yet recent clinical trials have demonstrated that early favorable patient responses are not durable, which has been attributed to drug resistance. The complex and diverse nature of the drug resistance mechanisms calls for a systematic approach to define new treatment paradigms to alleviate resistance to angiogenesis inhibitors. The overall objective of the project is to provide a preclinical foundation to design multidrug combination regimens that will overcome resistance to angiogenesis inhibitors and further ensure that coadministered cytotoxic drugs will reach tumors in sufficient amounts. To accomplish this objective, three Aims are proposed that describe a series of pharmacokinetic (PK) and pharmacodynamic (PD) investigations based on the properties of the drugs in tumors. Aim 1 studies will derive antiangiogenic drug resistant brain tumors in vivo and compare the tumor accumulation of the cytotoxic drug, temozolomide (TMZ) in sensitive and resistant tumors. The expression of genes and proteins relevant to angiogenesis will be monitored to create a resistance profile. Initial Aim 2 studies, again utilizing drug resistant tumors, will evaluate multitargeted drug combinations that interfere with angiogenesis by inhibiting targets on the cell surface and intracellularly. The drug combinations selected will be, in part, based on the resistance profiles determined in Aim 1. Upon identifying multitargeted drug combinations that suppress resistance, a final set of studies will be undertaken to analyze TMZ tumoral delivery and the process referred to as vascular normalization, a hallmark of effective drug delivery. As in Aim 1, PK (i.e. drug concentrations) and PD (gene and protein expression) measurements will be obtained in Aim 2 to provide a robust database to formulate PK/PD models for the effective combinations, which is the goal of Aim 3. Specifically, we will build physiologically-based PK/PD models that offer a means to be extrapolated to patients so that PK and PD endpoints can be predicted in brain tumors. The quantitative pharmacological approach underlying the project enables a more seamless pipeline of information to flow into the clinic that hopefully will provide a rational paradigm to design complex multidrug regimens. PUBLIC HEALTH RELEVANCE: Recent clinical studies indicate that the effectiveness of antiangiogenic drugs against solid tumors is temporary due to the development of drug resistance. By using preclinical brain tumor models resistant to angiogenesis inhibitors we will develop targeted drug combinations that overcome resistance, and further, enable coadministered cytotoxic drugs to be successfully delivered to the tumor. Quantitative pharmacological models will be derived and extrapolated to patients so that rational and effective multidrug therapy can be implemented in patients.

描述（由申请人提供）：实体瘤的生长和侵入性高度取决于血管生成或形成新的肿瘤血管的过程。因此，抗血管生成药物的开发非常重要，但是最近的临床试验表明，早期有利的患者反应不持久，这归因于药物耐药性。耐药性机制的复杂和多样性要求采用一种系统的方法来定义新的治疗范式以减轻对血管生成抑制剂的抗性。该项目的总体目的是为设计多药组合方案提供临床前的基础，以克服对血管生成抑制剂的耐药性，并进一步确保均匀的细胞毒性药物将以足够的量达到肿瘤。为了实现这一目标，提出了三个目的，描述了一系列基于肿瘤中药物特性的药代动力学（PK）和药效学（PD）研究。 AIM 1研究将在体内得出抗血管生成药物抗药性脑肿瘤，并比较敏感和抗性肿瘤中细胞毒性药物，替莫唑胺（TMZ）的肿瘤积累。将监测与血管生成相关的基因和蛋白质的表达，以创建抗性特征。最初的目标2研究再次利用耐药性肿瘤，将通过抑制细胞表面上的靶标和细胞内评估多静脉的药物组合，从而干扰血管生成。所选的药物组合将部分基于目标1中确定的耐药性曲线。在识别抑制耐药性的多核药物组合后，将进行最终的研究以分析TMZ肿瘤递送，并被称为血管归一化的过程，这是有效药物递送的标志。与目标1一样，将在AIM 2中获得PK（即药物浓度）和PD（基因和蛋白质表达）测量值，以提供一个强大的数据库，以制定有效组合的PK/PD模型，这是AIM 3的目标3。具体而言，我们将在生理上构建了介绍的PK/PD模型，这些模型将构建一个可以使患者构建的手段，以使其逐渐被置于脑海中，以使PD和PD分类为PK和PK。该项目基础的定量药理学方法使更无缝的信息管道流入诊所，希望能够为设计复杂的多药疗法提供合理的范式。 公共卫生相关性：最近的临床研究表明，由于耐药性的发展，抗血管生成药物对实体瘤的有效性是暂时的。通过使用对血管生成抑制剂抗性的临床前脑肿瘤模型，我们将开发靶向的药物组合，以克服耐药性，进一步使能够成功地递送到肿瘤中。定量药理学模型将被得出并推送给患者，以便在患者中可以实施合理有效的多药治疗。