| Hypoxia is a pathophysiologic consequence of structurally and functionally disturbed microcirculation in tumors and is associated with tumor propagation, malignant progression, and resistance to therapy. Nude mice bearing human head and neck squamous cell carcinoma (HNSCC) xenografts A253 and FaDu were treated with combination chemotherapy using irinotecan (CPT-11) and 5-fluorouracil (FUra) or 5-methylselenocysteine (MSC). A253 xenografts were found to consist of 30% well-differentiated avascular and 70% poorly differentiated regions with low microvessel density (MVD, 10/400X), while FaDu xenografts were found to consist of uniformly poorly differentiated regions with higher MVD (19/400X) and were more sensitive to therapy. Studies were performed to test the following hypotheses: (i) Do avascular, differentiated and thus possibly hypoxic regions in A253 hinder drug diffusion and distribution allowing some proliferating tumor cells to escape therapy? and, (ii) Can non-invasive blood oxygen level dependent (BOLD) functional magnetic resonance (fMR) imaging be used as a prognostic tool for determining chemotherapeutic efficacy?; Autoradiography results obtained after chemotherapy demonstrated that avascular well-differentiated A253 tumor regions with a hypoxic rim containing few proliferating cells showed five-fold lower 14C labeled CPT-11 concentrations compared to poorly differentiated areas. BOLD fMR imaging can identify regions containing neovasculature and chronic hypoxia and show prognostic differences within different response groups. Tumors that respond with complete remission do not recruit as many neoangiogenic vessels as the non-responders and show an increase in mean fMR signal intensity during therapy. MSC results in tumor vessel maturation as evidenced by increased vessel lumens. This has implications for better intratumoral drug delivery, therapy response and fMR imaging interpretations. (Abstract shortened by UMI.)... |
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