Normal brain tissue response to photodynamic therapy (PDT) must be quantified in order to implement PDT as a treatment of brain neoplasm. We therefore calculated the threshold for PDT-induced tissue necrosis in normal brain using Photofrin (porfimer sodium, Quadralogic Technologies Inc., Vancouver, BC) as the photosensitizer. The absolute light fluence-rate distribution for superficial irradiation and effective attenuation depth were measured in vivo using an invasive optical probe. Photosensitizer uptake in cerebral cortex was measured with chemical extraction and fluorometric analysis. Photodynamic therapy-induced lesion depths at various drug dose levels were measured as a biological end point. The PDT threshold for normal brain necrosis was calculated as in the magnitude of 10(16) photons/cm3. Thus normal rat brain is extremely vulnerable to PDT damage. This suggests that extra precautions must be exercised when PDT is used in brain.

Photodynamic therapy (PDT) has been used clinically for the treatment of malignant brain gliomas. However, the efficacy of this treatment to date has remained equivocal. This study focused on determining the sensitivity of 9L glio sarcoma in Fischer 344 rats to PDT with increasing doses of 632 nm light and making a comparison of the responses of normal and tumor tissue in the brain at these doses. This sensitivity was then correlated with the concentrations of Photoforin present in these tissues at the time of treatment. Our study indicates that the level of Photofrin in the tumor was 13 times that present in normal brain 48 h after injection. However, this selective localization of the photosensitizer was not reflected in a selective tissue response to PDT. There was minimal tumor response to a dose of 35 J cm-2, which has been reported previously to cause necrosis to the normal brain. Increasing energy dose levels resulted in an increased tumor response to PDT; however, normal tissue remained more sensitive than tumor tissue at all energy dose levels examined. These data indicate that, although Photofrin is retained to a significantly higher degree in the tumor than in the normal brain tissue, the normal brain is more sensitive than the tumor to PDT under the conditions outlined in this study.

We measured the response of normal brain and the human U87 glioma implanted in the brain of rats (n = 65) to photodynamic therapy (PDT) using Photofrin as the sensitizer. Normal brain and U87 tumor implanted within brain of athymic (nude) rats were subjected to PDT (12.5 mg/kg of Photofrin) at increasing optical energy doses (35 J/cm2, 140 J/cm2, 280 J/cm2) of 632 nm light. Photofrin concentration in tumor, brain adjacent to tumor and normal brain were measured in a separate population of rats. Twenty-four hours after PDT, the brains were removed, sectioned, stained with hematoxylin and eosin (H&E), and the volumes of the PDT-induced lesion measured. Photofrin concentration in tumor greatly exceeded that of normal brain and brain adjacent to tumor (> 20x). Both normal brain and U87 tumor exhibited superficial tissue damage with PDT at 35 J/cm2. However, both normal and tumor-implanted brain exhibited tissue damage with increasing optical dose. A heterogeneous pattern of pannecrosis along with a uniform volume of pannecrosis was detected in the tumor. In contrast, normal brain exhibited a uniform sharply demarcated volume of necrosis. Our data indicate that the U87 human brain tumor model and the normal brain in the athymic rat are sensitive to PDT and Photofrin with an optical dose-dependent response to treatment.

The effect of whole body hyperthermia and hypothermia in conjunction with photodynamic therapy (PDT) was determined on normal rat brain. Hyperthermia animals (Group I, n = 18) were warmed until their core body temperature reached 40 degrees C, (brain temperature, 39.7 +/- 0.5 degree C) and maintained at 40 +/- 1 degree C for 30 minutes prior to and after PDT. Hypothermia (Group II, n = 31) animals were cooled to 30 +/- 1 degree C (brain temperature, 29.3 +/- 0.4 degree C) for 1 hour. PDT treatment was performed, and the body temperature of the animals was maintained at 30 degrees C for 2 hours post-PDT. A population of animals was subjected to PDT under normothermic (Group III, n = 16; body temperature, 37 +/- 1 degree C; brain temperature, 36.7 +/- 0.8 degree C) conditions and treated in a manner identical to that of hyperthermic animals. PDT was performed with 17 J/cm2, 35 J/cm2, or 70 J/cm2 (100 mW/cm2). Photofrin (Quadralogic Technologies Ltd., Vancouver, Canada) (12.5 mg/kg) was injected intraperitoneally 48 hours prior to laser treatment on all three groups. Wet-dry weight measurements were obtained on a separate set of all three groups of animals (n = 27). Cortical lesion depths were measured, and pathological evaluation was made at 24 hours post-PDT. No difference in the wet-dry weight measurements or histopathology was present between the three groups of animals. Lesion depths for Group I animals did not significantly differ from Group III animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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