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.
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