Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to determine whether motexafin gadolinium (MGd), a known radiation sensitizer, could potentiate the effects of 5-aminolevulinic acid (ALA)-PDT. Human glioma (ACBT) spheroids (250 microm diameter) were incubated in 5-aminolevulinic acid (ALA) with and without MGd and irradiated with 635 nm light for a total light fluence of 6, 12, or 18 J cm(-2) delivered at a fluence rate of 5 mW cm(-2). Spheroid growth was monitored for a period of 4 weeks following each treatment. In another set of experiments, 400-500 microm diameter ACBT spheroids were implanted into a gel collagen matrix and subjected to ALA-PDT (fluence: 3 or 6 J cm(-2)), MGd, or a combination of ALA-PDT and MGd. The migration distance of surviving glioma cells in each treatment group was recorded over a 5-day period. The results showed that MGd interacted with PDT in a synergistic manner resulting in greater cytotoxicity than that achievable with either treatment modality alone. The degree of synergism was shown to increase with increasing light fluence. At the highest light fluence investigated (18 J cm(-2)), the percentage of spheroids demonstrating growth 4 weeks following exposure to MGd, ALA-PDT, or MGd + ALA-PDT was 100%, 75%, and 15%, respectively. The results of cell migration studies revealed that the combination of PDT and MGd produced a significant inhibitory effect on glioma cell migration: the addition of MGd resulted in an approximately three times reduction in migration distance compared with PDT alone. Overall, the results suggest that MGd can potentiate both the cytotoxic and migration inhibitory effects of ALA-PDT and hence, this combined therapeutic approach has the potential to extend treatment volumes in patients with malignant gliomas.