Subclinical photodynamic therapy treatment modifies the brain microenvironment and promotes glioma growth

Photodynamic therapy (PDT) has been clinically investigated as an adjuvant local therapy for brain tumors. Therapeutic interventions intended to promote tumor cell death,an also promote changes in the tumor microenvironment hat could favor tumor growth. We have previously shown hat PDT can activate pro-angiogenic factors in the normal rodent brain. This study seeks to further elucidate the effects of subtherapeutic doses of Photofrin-PDT on normal train and to establish a mouse model for studying glioma progression in an environment modified by oxidative stress. :Photofrin was administered to nude mice, and a defined inracranial area was illuminated with laser to deliver an optical dose equivalent to 80 J/cm(2). Three and 7 days after PDT, mice were sacrificed and brains were fixed and anayzed by immunohistochemistry. PDT treatment resulted in transient increase in cell proliferation, associated with a robust activation of astrocytes and microglia in the treated region, without causing substantial cell death. To test how his modified environment would affect glioma growth, human glioblastoma U87 cells were implanted in the PDT-treated hemisphere or in the control brain subjected to,ham surgery. Significantly larger tumors were observed after 3 weeks in the PDT treated brains relative to control treatment. Our results indicate that subclinical Photofrin-PDT locally alters the brain homeostasis without inflicting significant disruption to the tissue architecture, providing a model to study the effects of the microenvironment on glioma growth, with implications for the optimization of the clinical use of PDT for brain tumors. (c) 2007 Wiley-Liss, Inc.