This application's long term objectives are to explore, in depth, a novel method for chronically administering and increasing drug delivery to malignant brain tumors. convection-enhanced interstitial delivery (CEID) bypasses the blood-brain barrier (BBB) by infusion into the interstitial space, after which drug distribution occurs in two phases: a convection (pressure driven) phase and a diffusion (concentration driven) phase. Manipulating the infusion rate and/or drug concentration provides control over local tissue concentration. We first propose to define the limits of CEID by measuring the pharmacokinetics of 6 model compounds varying in size from 60 to 2.8 x 106 Daltons in RG-2 rat gliomas. For each compound, we will determine the halftime for the convection and diffusion components to reach equilibrium and the volume of distribution at equilibrium. We will measure pharmacokinetic parameters that most affect local drug concentration, including the efflux constant across capillaries and the influx and efflux constants across normal brain and RG-2 glioma cells. Drug distribution at steady state after CEID will be compared to IV delivery. Finally, quantitative autoradiography will be used to construct 3 dimensional maps of drug concentration in tumor and surrounding brain and to construct a model for predicting drug delivery parameters to brain tumors by CEID. Second, we will delivery antisense oligonucleotides (ODN) against VEGF and bFGF to ASV-induced gliomas in dogs to suppress tumor angiogenesis. Like human gliomas, ASV-induced gliomas have variable histology and permeability. We will measure tumor permeability using CT and test the accuracy of the pharmacokinetic model to predict local tissue drug concentrations. We will individualize the concentration of ODN to be administered and treat ASV-gliomas with antisense ODN against VEGF and bFGF. Outcome will be measured with serial CT studies of tumor size and permeability, and postmortem studies of VEGF and bFGF expression and microvascularity with Factor VIII staining. ODN Neurotoxicity will be evaluated with CEID infusions into normal dogs. Once the model is validated, the absence of neurotoxicity established, and we confirm suppression of tumor growth by chronic CEID infusion of antisense ODNs, we will begin Phase I studies in patients with malignant gliomas. Subjects will receive individualized doses of ODNs. Study design will be that of dose escalation with individualized ODN concentrations based on CT permeability studies, with outcome measures for neurotoxicity and tumor size. We expect to develop CEID as a new method of drug delivery to malignant gliomas for future use in Phase II trials.
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