Combination Therapies for Cancer Treatment

癌症治疗的联合疗法

基本信息

批准号：
8391071
负责人：
DAVID J WAXMAN
金额：
$ 30.85万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-16 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391071
关键词：
Abbreviations Advanced Development Advanced Malignant Neoplasm Agonist Angiogenesis Inhibition Angiogenesis Inhibitors Angiopoietin-2 Antineoplastic Agents Apoptotic Area Under Curve Blood Vessels Blood flow Caliber Cell Death Cell secretion Cells Characteristics Clinic Combined Modality Therapy Cyclophosphamide Cytochrome P450 Cytosine deaminase Cytotoxic agent Doxorubicin Drug Combinations Drug Delivery Systems Drug Exposure Drug Interactions Drug Targeting Drug resistance Endothelial Cells Endothelin Receptor Endothelin Receptor Antagonist Endothelin-1 Equilibrium Exposure to Fibroblast Growth Factor 2 Flucytosine Gene Targeting Gene-Directed Enzyme Prodrug Therapy Goals Growth Factor Heterogeneity Human Hypoxia IL8 gene Ifosfamide Integration Host Factors Interleukin-8 Liver Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Modeling Outcome PDGFRB gene Pathway interactions Patients Pattern Pericytes Pharmaceutical Preparations Pigment Epithelium Plasminogen Activator Inhibitor 1 Platelet-Derived Growth Factor Receptor Prodrugs Production Proliferating Proliferating Cell Nuclear Antigen Prostate-Specific Antigen Schedule Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Starvation Testing Therapeutic Thrombospondin 1 Toxic effect Treatment Efficacy Tumor Angiogenesis Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Patency Vasodilation Xenograft procedure antiangiogenesis therapy base cancer therapy cell killing chemotherapeutic agent chemotherapy cytotoxic cytotoxicity density design drug development follow-up gliosarcoma human TERT protein improved indexing inhibitor/antagonist macrophage neoplastic cell neovascularization novel pigment epithelium-derived factor public health relevance receptor response subcutaneous therapeutic effectiveness tumor tumor growth uptake weapons

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy using cytotoxic drugs is presently the most commonly used weapon in the treatment of advanced cancer. However, the therapeutic efficacy of cancer chemotherapeutic agents is limited by factors such as tumor heterogeneity, host toxicity and drug resistance. Recent advances in drug development have provided new opportunities to improve cancer therapy using drugs that target the tumor vasculature and inhibit tumor angiogenesis. To date, however, the survival benefit of these angiogenesis inhibitors has been rather modest and efforts to improve activity by combination with conventional chemotherapeutic drugs have been only partially successful. The overall goal of this project is to develop novel, more effective approaches to combining angiogenesis inhibitors with traditional cancer chemotherapeutics, building on progress made in the last project period in studies using the VEGF receptor-selective tyrosine kinase inhibitor axitinib and the liver cytochrome P450-activated anti-cancer prodrug cyclophosphamide. The major aims of this proposal are: 1) to elucidate the mechanism whereby anti-angiogenic drug treatment blocks tumor regression induced by metronomic cyclophosphamide treatment and then devise alternative therapeutic approaches that circumvent this block; 2) to investigate the use of provascular strategies to enhance tumor delivery of cancer chemotherapeutic drugs given in conjunction with anti-angiogenesis; 3) to harness the anti-vascular effects of anti-angiogenic drugs so as to increase tumor cell exposure to cytotoxic drugs administered intratumorally via an intratumoral 'trapping' (enhanced drug retention) mechanism; and 4) to investigate the impact of changes in tumor microvessel density, neovascularization and vascular maturity on responsiveness to the combination of anti-angiogenic drug treatment with chemotherapy. Together, these studies will elucidate ways to increase responsiveness to anti-angiogenic drugs by combination with conventional chemotherapeutic agents in a way that improves overall therapeutic activity, and will thereby advance the development of anti-cancer therapies.

描述（申请人提供）：使用细胞毒性药物的化疗是目前治疗晚期癌症最常用的武器。然而，癌症化疗药物的治疗效果受到肿瘤异质性、宿主毒性和耐药性等因素的限制。药物开发的最新进展为使用靶向肿瘤血管系统和抑制肿瘤血管生成的药物改善癌症治疗提供了新的机会。然而，迄今为止，这些血管生成抑制剂的生存益处相当有限，并且通过与常规化疗药物组合来提高活性的努力仅取得了部分成功。该项目的总体目标是在上一个项目期间使用 VEGF 受体选择性酪氨酸激酶抑制剂阿西替尼和肝细胞色素 P450 的研究取得的进展的基础上，开发新的、更有效的方法将血管生成抑制剂与传统癌症化疗药物相结合。活化的抗癌前药环磷酰胺。该提案的主要目的是：1）阐明抗血管生成药物治疗阻断节律环磷酰胺治疗诱导的肿瘤消退的机制，然后设计出绕过这种阻断的替代治疗方法； 2) 研究使用促血管策略来增强与抗血管生成联合给予的癌症化疗药物的肿瘤递送； 3) 利用抗血管生成药物的抗血管作用，以通过瘤内“捕获”（增强药物保留）机制增加肿瘤细胞对瘤内施用的细胞毒性药物的暴露； 4) 研究肿瘤微血管密度、新生血管形成和血管成熟度的变化对抗血管生成药物与化疗联合治疗反应的影响。总之，这些研究将阐明如何通过与传统化疗药物联合来提高抗血管生成药物的反应性，从而提高整体治疗活性，从而推动抗癌疗法的发展。