TOPOTECAN BY INTRACEREBRAL CLYSIS FOR BRAIN TUMORS

拓扑替康脑内裂解治疗脑肿瘤

• 批准号: 6729887
• 负责人: JEFFREY N BRUCE
• 金额: $ 46.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729887
• 关键词: astrocytoma; brain neoplasms; clinical trial phase I; drug administration routes; drug delivery systems; drug screening /evaluation; glioma; histopathology; human subject; human therapy evaluation; immunocytochemistry; implant; injection /infusion; magnetic resonance imaging; medical implant science; neoplasm /cancer chemotherapy; patient oriented research; radiography; statistics /biometry; tissue /cell culture; topotecan; western blottings

As with most solid tumors, clinical efficacy with cytotoxic chemotherapy compounds has been discouraging for malignant gliomas, mostly because of systemic drug toxicities and delivery limitations. Because they are locally invasive and rarely metastasize, malignant gliomas have features of a local-regional disease that make them uniquely amenable to new strategies of regional drug delivery. Intracerebral clysis (ICC) is a novel drug delivery strategy that utilizes a microinfusion pump to establish a positive pressure gradient in the brain via an implanted catheter. The pressure gradient produces convective forces that distribute a therapeutic agent throughout the tumor and surrounding interstitial space in the brain. Our preliminary data has shown that glioma cells are sensitive to topoisomerase I inhibitors including topotecan at levels that can be achieved in vivo with ICC. Additionally, topotecan by ICC is expected to have reduced toxicity by virtue of reduced topoisomerase I levels in normal brain compared to gliomas. Although ineffective in clinical trials due to systemic toxicity, topotecan has been safe and effective in our rat glioma model using ICC. The safe use of ICC as a delivery method has already been validated in early human trials. These findings lead us to hypothesize that topotecan delivered by ICC will increase survival in patients with primary malignant brain tumors. Furthermore, non- invasive radiographic methods of monitoring drug distribution and treatment response have been developed which will maximize its clinical application. These data lead to the Specific Aims which are: (1) to evaluate the safety and efficacy of ICC therapy with topotecan in patients with refractory and progressive primary malignant brain tumors; (2) to apply advanced MR imaging as a non-invasive means of optimizing treatment parameters and determining volume of drug distribution with ICC; and (3) determine whether the expression of the topoisomerase target in the tumor influences its response to topotecan by analyzing tumor histopathology, topoisomerase I expression, and in vitro drug sensitivity.

与大多数实体瘤一样，细胞毒性化疗化合物对恶性胶质瘤的临床疗效一直令人沮丧，主要是因为全身药物毒性和递送限制。由于恶性胶质瘤具有局部侵袭性且很少转移，因此它们具有局部区域疾病的特征，这使得它们独特地适合区域药物递送的新策略。脑内灌注（ICC）是一种新型的药物递送策略，其利用微输注泵通过植入的导管在脑中建立正压力梯度。压力梯度产生对流力，其将治疗剂分布在整个肿瘤和脑中的周围间隙空间中。我们的初步数据表明，胶质瘤细胞是敏感的拓扑异构酶I抑制剂，包括拓扑替康的水平，可以在体内实现与ICC。此外，与神经胶质瘤相比，由于正常脑中拓扑异构酶I水平降低，预计ICC的拓扑替康毒性降低。虽然由于全身毒性在临床试验中无效，但拓扑替康在我们使用ICC的大鼠胶质瘤模型中安全有效。ICC作为一种分娩方法的安全使用已经在早期的人体试验中得到验证。这些发现使我们假设，拓扑替康提供的ICC将增加生存原发性恶性脑肿瘤患者。此外，已经开发了监测药物分布和治疗反应的非侵入性放射照相方法，这将使其临床应用最大化。这些数据导致的具体目的是：（1）评价ICC与拓扑替康治疗难治性和进展性原发性恶性脑肿瘤患者的安全性和有效性;（2）应用先进的MR成像作为优化治疗参数和确定ICC药物分布体积的非侵入性手段;和（3）通过分析肿瘤组织病理学、拓扑异构酶I表达和体外药物敏感性来确定肿瘤中拓扑异构酶靶标的表达是否影响其对拓扑替康的反应。