TOPOTECAN BY INTRACEREBRAL CLYSIS FOR BRAIN TUMORS

与大多数实体肿瘤一样，细胞毒性化疗化合物对恶性胶质瘤的临床疗效令人沮丧，主要是因为全身药物毒性和递送限制。因为恶性胶质瘤是局部侵袭性的，很少转移，所以它们具有局部-区域疾病的特征，这使得它们独特地适应于新的区域药物递送策略。脑内灌肠（ICC）是一种新的药物输送策略，利用微输液泵通过植入导管在大脑中建立正压梯度。压力梯度产生对流力，使治疗剂分布在整个肿瘤和周围脑间质空间。我们的初步数据表明，胶质瘤细胞对拓扑异构酶I抑制剂（包括拓扑替康）敏感，其水平可以通过ICC在体内实现。此外，与胶质瘤相比，经ICC处理的拓扑替康在正常脑中的拓扑异构酶I水平降低，预计其毒性降低。虽然拓扑替康由于全身毒性在临床试验中无效，但在我们使用ICC的大鼠胶质瘤模型中是安全有效的。ICC作为一种安全的递送方法已经在早期人体试验中得到验证。这些发现使我们假设，通过ICC给药的拓扑替康将增加原发性恶性脑肿瘤患者的生存率。此外，监测药物分布和治疗反应的非侵入性放射学方法已经开发出来，这将最大限度地提高其临床应用。这些数据导致了具体的目的是：(1)评估拓扑替康联合ICC治疗难治性进展性原发性恶性脑肿瘤患者的安全性和有效性；(2)应用先进的磁共振成像技术作为优化治疗参数和确定ICC药物分布体积的无创手段；(3)通过分析肿瘤组织病理学、拓扑异构酶I的表达和体外药物敏感性，确定拓扑异构酶靶点在肿瘤中的表达是否影响其对拓扑替康的反应。

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.