L-DOPA preloading increases the uptake of borophenylalanine in C6 glioma rat model: A new strategy to improve BNCT efficacy

Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on B-10(n, alpha)Li-7 reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of B-10 nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for B-10-drug 4-dihydroxy-borylphenylaianine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model. Methods and Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Two L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography. Results: L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples. Conclusions: This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms. (C) 2008 Elsevier Inc.