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Background and Objective Achieving local control of gliomas with photodynamic therapy (PDT) requires the delivery of adequate light fluences to depths of 1–2 cm in the resection margin where the majority of local recurrences originate. This is clinically impractical with current single-shot, intraoperative PDT treatments due to the length of time required to deliver adequate fluences. Multiple or extended treatment protocols would therefore seem to be required. The response of human glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT using single or, repetitive light delivery protocols was investigated at both low and ultra low fluence rates. Study Design/Materials and Methods Human glioma spheroids (400 μm diameter) were subjected to sub-threshold light fluence (1.5, 3, or 6 J cm−2) ALA–PDT consisting of four light delivery schemes: single treatment given over either 1 or 24 hours, repetitive treatment given either as four 1 hour light treatments separated by a 4 day interval, or 24 hours light delivery, consisting of four 24 hours treatments separated by a 3 day interval. Treatment efficacy was evaluated using a growth assay. In some cases, confocal microscopy was used to image cell viability. Results The repetitive and single light treatment protocols were most effective when delivered at ultra low (μW cm−2) fluence rates. In all cases, growth inhibition was light dose-dependent. The repetitive ultra low fluence rate treatment (1.5 J cm−2; irradiance = 17 μW cm−2) light delivery protocol was the most effective resulting in total growth inhibition during the 2-week observation period. Conclusion Ultra low light fluence rate ALA–PDT results in significant spheroid growth inhibition. Repeated administration of ALA was required during repetitive and/or protracted single PDT treatment protocols. The existence of a lower fluence rate limit, below which the efficacy of threshold light fluences diminish was not found in these studies.

Abstract. We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS 2a -photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS 2a (PDT effect), bleomycin (chemotherapy effect), or AlPcS 2a þ bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5 J∕cm 2 @ 5 mW∕cm 2 ) AlPcS 2a -PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations-incubation of F98 cells in 0.1 μg∕ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5 J∕cm 2 together with 0.25 μg∕ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS 2a -mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas.

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Indigofera zollingeriana Miq (I. zollingeriana) is a widely grown tree in Vietnam. It is used to cure various illnesses. The purpose of this study was to investigate the chemical constituents of an I. zollingeriana extract and test its anticancer activity on hepatocellular cells (Huh7 and HepG2). The experimental results of the analysis of the bioactive compounds revealed that β-sitosterol (β-S) and β-sitosterol-glucoside (β-SG) were the main ingredients of the I. zollingeriana extract. Regarding anticancer activity, the β-S and β-SG of I. zollingeriana were found to exhibit cytotoxic effects against HepG2 and Huh7 cells, but not against normal human primary fibroblasts. The β-S was able to inhibit the proliferation of HepG2 and Huh7 cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values of 6.85 ± 0.61 µg/mL and 8.71 ± 0.21 µg/mL, respectively (p < 0.01), whereas the β-SG IC50 values were 4.64 ± 0.48 µg/mL for HepG2 and 5.25 ± 0.14 µg/mL for Huh7 cells (p < 0.01). Remarkably, our study also indicated that β-S and β-SG exhibited cytotoxic activities via inducing apoptosis and activating caspase-3 and -9 in these cells. These findings demonstrated that β-S and β-SG from I. zollingeriana could potentially be developed into promising therapeutic agents to treat liver cancer.