L-DOPA preloading increases the uptake of borophenylalanine in C6 glioma rat model: a new strategy to improve BNCT efficacy.
OBJECTIVE
Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on (10)B(n,alpha)(7)Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of (10)B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for (10)B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model.


METHODS
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.
Capuani
Silvia
S
Physics Department, Sapienza University of Rome, Italy; Enrico Fermi Center, Rome, Italy. silvia.capuani@roma1.infn.it
Gili
Tommaso
T
Bozzali
Marco
M
Russo
Salvatore
S
Porcari
Paola
P
Cametti
Cesare
C
D'Amore
Emanuela
E
Colasanti
Marco
M
Venturini
Giorgio
G
Maraviglia
Bruno
B
Lazzarino
Giuseppe
G
Pastore
Francesco S
FS
D000818:Animals; D001896:Boron Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000378:metabolism* / Q000532:radiotherapy; D015259:Dopamine Agents / Q000008:administration & dosage* / Q000494:pharmacology; D005910:Glioma / Q000097:blood / Q000378:metabolism* / Q000532:radiotherapy; D007980:Levodopa / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats
C436045:4-dihydroxyborylphenylalanine; D001896:Boron Compounds; D015259:Dopamine Agents; D007980:Levodopa; D010649:Phenylalanine