Tumor hypoxia influences efficacy of radiation therapy and some chemotherapy, and affects metastatic potential and angiogenesis. We have used in vivo experimental observations and data-based theoretical models to define quantitatively the physiological factors leading to chronic and acute hypoxia in the R3230AC mammary carcinoma, and to test strategies to improve PO2. Model predictions agreed well with experiment and led to development of novel means for reducing tumor hypoxia. To test the broader applicability of this approach, we propose to examine other tumor models, and to consider glucose transport.
Specific Aim 1 : We will study an intermediately hypoxic fibrosarcoma (RFSa) and the relatively normoxic 9L glioma. Hypotheses: 1) Differences in P02 between these tumors and the strongly hypoxic R3230AC can be related to microvascular anatomy, O2 consumption and/or perfusion. 2) Glucose levels influence 02 transport in tumors.
Specific Aim 2 : We have identified a novel method to reduce hypoxia by combining mild hyperglycemia with hyperoxic gas breathing. We will evaluate additional strategies for metabolic manipulation and pharmacologic right-shifting of the hemoglobin saturation curve. Hypothesis: Combinations of strategies will further improve 02 delivery.
Specific Aim 3 : We will use tumor cells, stably transfected with green fluorescence protein under control of hypoxia and/or stress inducible promoters, to determine the in vivo conditions (PO2, pH and glucose concentrations) that stimulate promoter activity. Cells with high and low levels of reporter gene expression will be FACS isolated from tumors and assessed for patterns of gene expression. The physiologic conditions correlated with altered reporter gene expression in vivo will be reproduced in vitro, and patterns of gene expression between control, tumor simulated conditions and FACS isolated tumor cells will be compared. Hypothesis: Variations in tumor microenvironment, as measured by differences in PO2, pH and/or glucose will be correlated with changes in gene expression. The results of this work will have implications for: 1) Understanding quantitatively the processes that control both 02 and glucose transport in tumors, 2) Designing novel approaches for reduction of tumor hypoxia and 3) Identifying the physiologic conditions in tumors leading to altered gene expression. This will have important implications for gene therapy strategies that utilize features of the tumor microenvironment as a promoter switch.
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