Opening of the Blood Brain Barrier to Antitumor Agents

抗肿瘤药物打开血脑屏障

• 批准号: 7383752
• 负责人: EDWARD A. NEUWELT
• 金额: $ 61.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383752
• 关键词: Acetylcysteine; Address; Affect; Animal Model; Aorta; Appearance; Area; Attention; BR96-Doxorubicin Immunoconjugate; Binding; Blood - brain barrier anatomy; Blood Platelets; Bone Marrow; Brain; Brain Neoplasms; Bystander Effect; Carboplatin; Carboplatin/Melphalan; Carotid Arteries; Cells; Central Nervous System Lymphoma; Central Nervous System Neoplasms; Chemoprotection; Chemoprotective Agent; Chemotherapy-Oncologic Procedure; Chlorambucil; Clinic; Clinical; Combination Chemotherapy; Combined Modality Therapy; Descending aorta; Development; Dextrans; Disruption; Dose; Doxorubicin; Drug Delivery Systems; Extracellular Matrix; Ferumoxtran-10; Funding; Goals; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Hematogenous; Heterogeneity; High Dose Chemotherapy; Human; Image; Immunoconjugates; Implant; In Situ; Infusion procedures; Internal carotid artery structure; Iron; Joints; Label; Laboratories; Laboratory Study; Leptomeningeal Neoplasms; Literature; Magnetic Resonance; Magnetic Resonance Imaging; Maximum Tolerated Dose; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Methodology; Methods; Modeling; Modification; Myelosuppression; Neoplasm Metastasis; Neuraxis; Nodule; Nude Rats; Numbers; Operative Surgical Procedures; Patients; Perfusion; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Program Review Group; Progress Review Group; Prophylactic treatment; Protein Binding; Proteins; Protocols documentation; Public Health; Purpose; Radiation; Radiation therapy; Radiosurgery; Rattus; Role; Route; Saline; Serum Proteins; Standards of Weights and Measures; Sulfhydryl Compounds; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Translating; Treatment Efficacy; Treatment Protocols; Tylenol; United States National Institutes of Health; Xenograft Model; antitumor agent; base; brain research; chemotherapeutic agent; chemotherapy; day; dextran; granulocyte; implantation; improved; iron oxide; irradiation; lung Carcinoma; lung small cell carcinoma; matrigel; nanoparticle; neoplastic cell; neuro-oncology; neurotoxicity; novel; novel therapeutics; particle; prevent; programs; response; sodium thiosulfate; spine bone structure; targeted delivery; tumor; tumor growth; vertebral artery

Therapy for brain tumors is complicated by the blood-brain barrier (BBB), which impedes delivery of chemotherapeutic agents to the central nervous system (CNS). Osmotic BBB disruption (BBBD) is a method to deliver agents across the BBB to infiltrating tumor cells. The Brain Tumor Program Review Group (PRG) recently identified the areas of drug delivery,targeted chemotherapy, imaging, and the BBB as priorities forresearch in CNS metastases. During the previous funding period, we addressed the PRG points by showing that route of delivery of a tumor-specific immunoconjugate(BR96-DOX) is directly related to survival in an implanted metastasis model, and combination protocols with radiotherapy further improved survival. The current question is how to further extend this paradigm in the laboratory and the clinic by focusing on the BBB, ~to examine issues in delivery of antitumor agents to brain tumors and to evaluate the efficacy of therapeutic approaches. In Aim 1,we plan to expand our current implanted CNS metastatic tumor model in nude rats to a hematogenous CNS metastatic model. We propose to assess tumor growth by using a novel magnetic resonance (MR) imaging approach using super- paramagnetic iron particles to detect CNS tumors prior to conventionalimaging. Aim 2 will investigatetherapeutic approaches for CNS metastases. We will determine if protein bindingimpactsCNS chemotherapeutic delivery and efficacy. Additionally, we will assess targeted delivery of the BR96-DOX immunoconjugate used in conjunction with standard chemotherapy and external beam radiotherapy. In Aim 3 we will test the hypothesis that the thiol N- acetylcysteine (NAC) with or without sodium thiosulfate (STS), may ameliorate the bone marrow toxicity of combination chemotherapy/radiation protocols without compromising CNS chemotherapyefficacy. Finally,in Aim 4 a clinical phase 1trial of NAC is proposed. We hypothesize that NAC administered i.a. caudallyin the aorta will be safe in patients and prevent myelosuppresion in combination with high dose chemotherapy given into the vertebral and carotid arteries cephalad. Our overall hypothesis is that CNS enhanced delivery and combination therapies in models of CNS metastasis will increase anti-tumor efficacy as assessed by serial MR imaging, tumor volumetrics, and survival, whileminimizingtoxicity withchemoprotection. Laboratory studies of BBBD-enhanced chemotherapy have been translated intoclinical trials, and excitingefficacy has been demonstrated in primary CNS lymphoma. This revised competitive renewal is the continuation of the original 1978 surgical CREG, and is responsive to the priorities established in July 2000 by the joint NINDS and NCI Brain Tumor PRG.

血脑屏障 (BBB) 阻碍了脑肿瘤的治疗 中枢神经系统（CNS）的化疗药物。渗透性 BBB 破坏 (BBBD) 是一种方法 将药剂穿过血脑屏障递送至浸润的肿瘤细胞。脑肿瘤计划审查小组 (PRG) 最近 确定药物输送、靶向化疗、成像和 BBB 领域为中枢神经系统研究的优先领域 转移。在上一个资助期间，我们通过展示交付路线来解决 PR​​G 点 肿瘤特异性免疫偶联物（BR96-DOX）与植入转移模型中的存活率直接相关， 与放射治疗的联合方案进一步提高了生存率。当前的问题是如何进一步 通过关注 BBB，在实验室和临床中扩展这一范式，〜检查交付中的问题 抗肿瘤药物治疗脑肿瘤并评估治疗方法的功效。在目标 1 中，我们计划扩展 我们目前在裸鼠中植入的中枢神经系统转移肿瘤模型为血行中枢神经系统转移模型。我们 提议通过使用新型磁共振（MR）成像方法来评估肿瘤生长，该方法使用超 顺磁性铁颗粒在常规成像之前检测中枢神经系统肿瘤。目标 2 将研究治疗方法 CNS 转移的方法。我们将确定蛋白质结合是否影响中枢神经系统化疗的传递和 功效。此外，我们将评估联合使用的 BR96-DOX 免疫缀合物的靶向递送 采用标准化疗和外照射放疗。在目标 3 中，我们将检验硫醇 N- 的假设 乙酰半胱氨酸（NAC）联合或不联合硫代硫酸钠（STS），可以改善骨髓毒性 联合化疗/放疗方案而不影响中枢神经系统化疗疗效。最后，瞄准 4 提议进行 NAC 临床 1 期试验。我们假设 NAC 执行了 i.a.尾侧在主动脉会 与高剂量化疗联合使用可确保患者安全并预防骨髓抑制 椎动脉和颈动脉位于头侧。我们的总体假设是中枢神经系统增强了传递和结合 通过连续 MR 成像评估，中枢神经系统转移模型中的治疗将提高抗肿瘤功效，肿瘤 体积和生存，同时通过化学保护最大限度地减少毒性。 BBBD 增强的实验室研究 化疗已转化为临床试验，在原发性中枢神经系统中已证实令人兴奋的疗效 淋巴瘤。此次修订后的竞争性更新是 1978 年原始手术 CREG 的延续，并且 响应 NINDS 和 NCI 脑肿瘤 PRG 于 2000 年 7 月联合制定的优先事项。

项目成果

Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging.

• DOI: 10.2214/ajr.10.5992
• 发表时间: 2011-10
• 期刊: AJR. American journal of roentgenology
• 作者: Hamilton BE;Nesbit GM;Dosa E;Gahramanov S;Rooney B;Nesbit EG;Raines J;Neuwelt EA
• 通讯作者: Neuwelt EA

Diagnosis of pseudoprogression using MRI perfusion in patients with glioblastoma multiforme may predict improved survival.

• DOI: 10.2217/cns.14.42
• 发表时间: 2014-11
• 期刊: CNS oncology
• 作者: Gahramanov S;Varallyay C;Tyson RM;Lacy C;Fu R;Netto JP;Nasseri M;White T;Woltjer RL;Gultekin SH;Neuwelt EA
• 通讯作者: Neuwelt EA

The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma.

α-V整合素抑制对髓母细胞瘤恶性特征的影响。

• DOI: 10.3171/2012.9.peds12268
• 发表时间: 2013
• 期刊: Journal of neurosurgery. Pediatrics
• 作者: Thompson,EricM;Whitney,NathanielL;Wu,YJeffrey;Neuwelt,EdwardA
• 通讯作者: Neuwelt,EdwardA

Acetaminophen enhances cisplatin- and paclitaxel-mediated cytotoxicity to SKOV3 human ovarian carcinoma.

• 发表时间: 2013-06
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Yinglin Wu;A. Neuwelt;L. Muldoon;E. Neuwelt

Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model.

• DOI: 10.1007/s11060-012-0942-0
• 发表时间: 2012-10
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Wu, Y. Jeffrey;Muldoon, Leslie L.;Gahramanov, Seymur;Kraemer, Dale F.;Marshall, Deborah J.;Neuwelt, Edward A.
• 通讯作者: Neuwelt, Edward A.