) The overall goal of this project is to optimize the suicide gene therapy approach to achieve maximum clinical benefit. This will be accomplished through the development of non-invasive imaging techniques and by devising the most efficient method for delivery of ganciclovir to the tumors of human subjects transfected with Herpes simplex virus thymidine kinase (HSVtk). Pharmacokinetic models will be constructed using analytical methodology based on liquid chromatography/mass spectrometry as the foundation for non-invasive imaging strategies for use in patients being treated with suicide gene therapy. We hypothesize that there is a relationship between systemic exposure of ganciclovir and concentrations that are found in tumors. Initial experiments will be performed using animal tumor models so that this hypothesis can be tested. In addition, all optimal dosing strategy will be defined, and the relationship between plasma and tumor concentrations will be determined. The n vivo metabolism of ganciclovir will be studied in order to ensure that it is not altered in the animal tumor models when compared with control animals. Ganciclovir metabolites that are found in tumor tissue will also be characterized and quantified. The experiments with animal models will lay the groundwork for phase I pharmacokinetic studies in patients with ovarian cancer and malignant mesothelioma. Extensive modeling will be performed in order to provide parameter estimates that describe the experimental data. These should permit predictions of, for example, likely dosing regimens and probable plasma drug levels using different dosing schedules or different routes of administration. An important component of this proposal involves the development of non-invasive methodology to assess the duration and distribution of gene expression. We propose to develop imaging methodology so that we can monitor HSVtk activity and thereby provide information that can be used to further improve this strategy. These studies will be performed using a new PET imaging technique to measure the thymidine kinase enzymatic activity. This study will have important implications for suicide gene therapies in general, and will validate novel technique for assessing gene transfer.
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