The term "metronomic" was recently introduced to describe continuous low-dose administration of chemotherapeutics following the discovery that this causes minimal side effects (Hanahan et al. 2000, J Clin Invest, 105(8), 1045-1047; Bisland et al. 2004, Photochem Photobiol, 80, 22-30). Metronomic dosing in PDT is proposed by analogy and the rationale is as a means to improve the tumor-specific response through cell death by apoptosis. We investigated the molecular mechanisms associated with apoptosis following ALA-PDT treatment in two brain glioma cell lines, namely U87 (human) and CNS-1 (rat) cells. We used the high energy of light at a short time (acute PDT) and the low energy of light at a long time of exposure (metronomic PDT) to treat both cell lines. To identify potential cell death pathways associated with metronomic PDT, microarray analysis of gene expression was conducted on RNA from glioblastoma cells with metronomic ALA-PDT. The apoptosis mechanism for metronomic ALA-PDT occurred via the inhibition of LTbetaR and the transcription factor NF-kappaB. This inhibition was ALA concentration dependent.