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Intratumoral Distributions
of Oxygen in PDT-Treated Murine Tumors and the Tumor Nodules of Patients
to Receive PDT
Busch, Theresa1,
Evans, Sydney1, Hahn, Stephen1,
Wileyto, E.1 and Koch, Cameron1
University of Pennsylvania, Philadelphia, PA1
Abstract-
Photodynamic therapy (PDT) requires the presence of oxygen to create
tissue damage. Hypoxia, either pre-existing or created during illumination,
can significantly limit tumor responses. Not known, however, is the
effect of the spatial distribution of oxygen on PDT outcome. Using the
hypoxia markers EF3 or EF5 the spatial distribution of oxygen can be
quantified in PDT-treated murine tumors or in the tumor nodules of patients
scheduled to receive PDT. Pre-clinical studies were carried out in the
radiation induced fibrosarcoma (RIF) tumor model treated with Photofrin
(5 mg/kg) PDT at 75 mW/cm2, 135 J/cm2. Hypoxia
during PDT was labeled by administering EF3 immediately before PDT illumination,
with tumor excision immediately after PDT. Hoechst 33342 was used to
label blood vessel perfusion at the time of tumor excision. After immunohistochemistry
and fluorescence microscopy, quantitative image analysis was performed
to characterize the intratumoral distribution of hypoxia. Control RIF
tumors were well-perfused and demonstrated low levels of EF3 binding;
minimal increase in hypoxia was found with increasing distance to a
perfused blood vessel. During PDT, hypoxia increased as a function of
increased distance to the nearest perfused blood vessel. Thus substantial
intratumoral heterogeneity in oxygenation was found. In clinical studies
utilizing EF5, intermediate hypoxia along with significant spatial heterogeneity
was found in nodules of colon carcinoma in a patient with disseminated
intraperitoneal disease. The nodules of two patients with gastrointestinal
stromal tumors contained low to intermediate EF5-labeled hypoxia. Ongoing
studies, both pre-clinical and clinical, investigate the significance
of intratumoral oxygen distribution in determining PDT response.
Keywords: hypoxia,
photodynamic therapy, EF3, EF5
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