Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid

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Object. Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the authors sought to discover whether its accumulation might be exploited for use in photoirradiation therapy of experimental brain tumors, without injuring normal or edematous brain.

Methods. Thirty rats underwent craniotomy and were randomized to the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for edema induction; 4) cortical cold injury with simultaneous administration of 5-ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous administration of Photofrin II (5 mg/kg body weight). Tumors were induced by cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours after irradiation, the brains were removed for histological examination.

Irradiation of brains after administration of 5-ALA resulted in superficial cortical damage, the effects of which were not different from those of the irradiation alone. Induction of cold injury in combination with 5-ALA and irradiation slightly increased the depth of damage. In the group that received irradiation after intravenous administration of Photofrin II the depth of damage inflicted was significantly greater. The extent of damage in response to 5-ALA and irradiation in brains harboring C6 tumors corresponded to the extent of tumor determined from pretreatment MR images.

Conclusions. Photoirradiation therapy in combination with 5-ALA appears to damage experimental brain tumors selectively, with negligible damage to normal or perifocal edematous tissue.

Article Information

Address reprint requests to: Walter Stummer, M.D., Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, 81366 Munich, Germany. email: wstummer@nc.med.uni-muenchen.de.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graph showing mean depths ± SDs of cortical damage observed after solitary laser irradiation (200 J/cm)2. Laser only group: six rats; laser irradiation (200 J/cm2) after intravenous administration 100 mg/kg of 5-ALA 6 hours earlier (ALA + Laser group: six rats); cortical cold lesion (Injury only group: six rats); simultaneous cold lesioning and administration of 100 mg/kg 5-ALA laser irradiation (200 J/cm2) 6 hours later (Injury + ALA + Laser group: six rats); and laser irradiation of normal cortex 6 hours after intravenous administration of 5 mg/kg Photofrin II (PF II + Laser group: six rats, *p < 0.01 compared with others).

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    Histological section showing various types of cortical damage encountered in response to photoirradiation therapy, in this case after simultaneous cold lesioning and administration of 5-ALA (100 mg/kg body weight) with laser irradiation (200 J/cm2) 6 hours later. a: Superficial coagulative necrosis; b: region of selective neuronal damage and margin of edema; c: circumscribed hemorrhage; and d: total depth of phototoxic damage. H & E, bar = 2 mm.

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    Upper Left: Histological section of a typical C6 tumor with measurement lines used for unequivocally determining tumor size. H & E, bar = 10 mm. Upper Right: Corresponding coronal MR image with measurement lines for estimating tumor size. Lower: Graph showing mean tumor dimensions as determined based on MR images and histological sections (mean ± SD in six rats).

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    Photomicrograph of a representative example for hemorrhagic tumor damage caused by irradiation with 100 J/cm2 of 635 nm laser light 6 hours after administration of 100 mg/kg 5-ALA. Note perilesional pallor of tissue. H & E, bar = 2 mm. Inset: Pretreatment MR image in the same animal.

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    Graph showing tumor depths as determined based on pretreatment MR imaging and extent of histological damage as determined from hematoxylin-eosin—stained brain sections 72 hours after PDT (3 hours: PDT 3 hours after administration of 5-ALA, six rats in each group, means ± SDs).

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