Survival of patients with malignant gliomas has not significantly improved in the past 40 years. The limitations imposed by the blood-brain barrier (BBB) on drug delivery to brain tumors have been a controversial and seemingly unresolvable issue. Current methods for measuring drug delivery to brain are not good for reactive chemical species, including most chemotherapeutic drugs, and are not applicable in humans. We have developed a noninvasive method of measuring BBB function in humans, but have been unable to use it to predict successful chemotherapeutic drug delivery. We propose to develop a method for using magnetic resonance spectroscopy (MRS) to measure blood-to-brain delivery of chemotherapeutic drugs. MRS is a highly specific method of analyzing chemical composition. In this application, the methods for using MRS will be developed by using tissue specimens, initially from an animal brain tumor model and then from human subjects. This application proposes a stepwise series of four projects, which when completed will establish the foundation for using in vivo MRS to noninvasively study chemotherapeutic drug delivery to brain tumor patients, which will then permit this heretofore unreconcilable variable to become a part of the design of clinical chemotherapy trials. This application has four specific aims. First, we will develop a method for using """"""""ideal"""""""" 13C labeled compounds to independently measure blood-to- tissue transport (K1), tissue plasma space (Vp), and tissue extracellular space (Ve), which are needed to unravel the behavior of the more complex chemotherapeutic drugs. Second, we will use MRS to determine the tissue pharmacokinetics of the 13C compounds along with two fluoropyrimidines: 5FU and FUdR. Third, we will use MRS to determine tissue pharmacokinetics of chemotherapeutic drugs of an established brain tumor chemotherapy regimen (PCV; procarbazine, CCNU, vincristine). The first three specific aims will be conducted in RG-2 rat gliomas,.and MRS measurements performed on plasma, brain, and RG-2 tumor specimens. In the fourth specific aim, we will study drug delivery in two groups of patients with malignant astrocytomas. One group will receive 13C urea and 5FU or FUdR, based on the outcome of the second specific aim. The other group will receive 13C urea, caffeine and PCV. Both groups of patients will also have BBB permeability measured with computed tomographic techniques. The data from the fourth Specific Aim will be insufficient to calculate delivery parameters, but will be evaluated to establish that (1) it is feasible to use MRS spectroscopy to make drug delivery measurements of chemotherapeutic drugs, and (2) noninvasive measurements of BBB permeability predict the amount of drug reaching the brain tumor. Both outcomes will lead to noninvasive ways of predicting and measuring delivery of chemotherapeutic drugs to brain tumors.
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