Malignant gliomas represent localized disease that has in the past been treated with systemic chemotherapy and external beam radiation. Our goal in this study is to provide more appropriate new measures of localized therapy through the use of interstitial chemotherapy. The latter will be greatly facilitated by a polymeric drug delivery system developed at our institution. This system has been shown capable of delivering a multitude of agents including amasacrine, a topoisomerase II inhibitor. In addition, many exciting agents are available in general oncology that have not been tried because of blood/brain barrier interference. We plan to perfect a model system for localized interstitial drug release through a polymer drug delivery device. We expect to test several synergistic cytotoxic, anti-antiogenesis and radiation sensitizing agents. All categories of drugs will be incorporated in the polymeric drug delivery system and tested both in vitro and in vivo. The amasacrine releasing devices have already shown positive effects both in animal studies and humans. These preliminary studies will be further expanded and a Phase I trial initiated. The evaluation of the polymeric drug delivery system will be a joint effort between projects 1, 2 and 4 and core units B, C and D. The kinetics of the drug delivery will be analyzed in vitro and in vivo with the help of Pharmacology Core C. Dr. Abernethy will perform mathematical modeling of the drug distribution and diffusion. The efficacy of the delivery devices will be evaluated by ramping up the nude mice experiments of Core B. Dr. Belliveau will collaborate on the development of radiation enhancers such as cis- and trans-platinum derivatives. These agents will be incorporated into the polymeric release system with special attention to those agents that have good antineoplastic activity but poor penetration through the blood brain barrier. In addition, drugs developed in the medicinal chemistry Core D and in project 2 will be included and tested both in vitro and in vivo. From these studies synergistic new modalities will be developed to improve the therapy of this lethal disease.
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