The long-term goal of this pre-clinical project is to develop and optimize new techniques for fluorescence-guided resection (FGR) and photodynamic therapy (PDT) of malignant brain tumors. FGR has the potential to improve brain tumor surgery, by detecting residual tumor after standard white-light resection, using protoporphyrin IX (PpIX) fluorescence resulting from administration of aminolevulinic acid, ALA, which we have previously shown to have high tumor specificity. A novel approach to PDT (metronomic: mPDT) will use ALA and light at low dose rates over an extended period. From preliminary work, we hypothesize that mPDT can selectively destroy tumor cells by apoptosis without damage to normal brain. FGR and mPDT will be investigated in brain tumors (human and murine) with complementary characteristics. The FGR and mPDT parameters will be optimized, both independently and together, using several outcome measures: histomorphometry and apoptosis imaging, in vivo bioluminescence imaging of tumor growth and response, and survival. Complementing these studies, current work showing the induction of angiogenesis by Photofrin-PDT will be extended, in both tumor and normal brain. Quantitative morphometric and histopathologic measures will be used, and the effect on tumor regrowth/survival will be determined, both with PDT alone and with PDT in combination with anti-angiogenic agents. These studies will also be done with ALA, hypothesizing that the mPDT will be non-angiogenic. In a final aim, the molecular aspects of ALA-mediated PDT will be investigated using glioma cell lines in vitro and comparing metronomic and acute, high-dose ALA-PDT, in order to provide a mechanistic understanding of the tumor cell responses and possible angiogenic effects. In summary, this project will substantially expand our knowledge and understanding of PDT of brain tumors and will provide significant data for the design of subsequent clinical trials (in Project 2).
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