TOPOTECAN BY INTRACEREBRAL CLYSIS FOR BRAIN TUMORS

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给药限制。由于恶性胶质瘤是局部侵袭性的，很少转移，因此具有局部区域性疾病的特征，这使得它们独特地服从于新的区域性药物输送策略。脑内灌肠(ICC)是一种新型的给药策略，它利用微量输液泵通过植入的导管在大脑中建立正压力梯度。压力梯度产生对流力，将治疗剂分布在整个肿瘤和大脑周围的间质空间。我们的初步数据显示，胶质瘤细胞对包括拓扑替康在内的拓扑异构酶I抑制剂的敏感性达到了在体内使用ICC所能达到的水平。此外，由于与胶质瘤相比，正常大脑中的拓扑异构酶I水平降低，ICC的Topotecan有望降低毒性。尽管由于全身毒性而在临床试验中无效，拓扑替康在使用ICC的大鼠胶质瘤模型中是安全有效的。ICC作为一种给药方法的安全性已经在早期的人体试验中得到了验证。这些发现使我们假设，ICC提供的拓扑替康将提高原发性恶性脑瘤患者的存活率。此外，还开发了监测药物分布和治疗反应的非侵入性放射学方法，这将使其在临床上得到最大限度的应用。这些数据产生了特定的目标：(1)评估Topotecan对难治性和进展性脑肿瘤患者ICC治疗的安全性和有效性；(2)应用先进的MR成像作为优化治疗参数和确定ICC药物分布量的无创性手段；以及(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，确定肿瘤中拓扑异构酶靶标的表达是否影响其对Topotecan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.