L-DOPA PRELOADING INCREASES THE UPTAKE OF BOROPHENYLALANINE IN C6
GLIOMA RAT MODEL: A NEW STRATEGY TO IMPROVE BNCT EFFICACY
*INFM-CNR CRS SOFT, Physics Department, ‘‘Sapienza’’ University of Rome, Italy;
Enrico Fermi Center, Rome, Italy;
Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy;
Department of Neurosurgery, Manchester University Hospital,
Manchester, United Kingdom;
Physics Department, ‘‘Sapienza’’ University of Rome, Italy;
Servizio Qualita’e Sieurezza della
Sperimentazione Animale, Istituto Superiore di Sanita`, Rome, Italy;
**Department of Biological Science, University ‘‘Rome III’’,
Department of Chemical Sciences, Laboratory of Biochemistry, University of Catania, Catania, Italy;
Department of Neurosurgery, University ‘‘Tor Vergata’’, Rome, Italy
Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on
Li reaction, for
the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufﬁcient intake of
B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for
B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was ﬁrst per-
formed in vitro and then extended to the animal model.
Methods and Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectros-
copy, 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 an-
imals 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 malig-
nant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport
mechanisms. Ó 2008 Elsevier Inc.
BNCT, C6-glioma, rat brain, L-DOPA, BPA, HPLC, MRI, Dielectric Spectroscopy.
Malignant gliomas are the most common primary intracranial
neoplasms in humans, accounting for about 78% of all malig-
nances of the central nervous system (1). More than 80% of
these tumors are considered high-grade (Grades 3 and 4) ac-
cording to the current World Health Organization criteria (2).
Anaplastic astrocitomas (Grade 3) and glioblastomas (Grade
4) are typically associated with a severe prognosis, with a me-
dian overall survival of 1–5 years (2). Despite advances in
microsurgical techniques, radiotherapy, and chemotherapy,
there has been little improvement in the clinical outcome of
patients suffering from these kinds of tumors.
Boron Neutron Capture Therapy (BNCT) (3–6) is a tech-
nique based on a targeted radiation approach, which repre-
sents an alternative adjuvant therapy for malignant gliomas.
It has already been used in patients with various types of
brain malignances, including glioblastomas (7–12), anaplas-
tic meningiomas (13), cerebral melanoma metastases (14),or
tumors recurrences in inoperable anatomic locations (15, 16).
In this context, a few Phase I (7, 8, 10, 11) and Phase II stud-
ies (8, 10) have consistently demonstrated no severe effects
of BNCT-related toxicity, and some preliminary evidence
of therapeutic effectiveness (7, 9, 12) has been presented.
From a technical point of view, BNCT is based on the
Reprint requests to: Dr. Silvia Capuani, Physics Department Uni-
versity ‘‘La Sapienza,’’ Piazzale Aldo Moro 2, 00185 Rome, Italy.
Tel/Fax: (+39) 06-49913928; E-mail: firstname.lastname@example.org
Conﬂict of interest: none.
Received March 31, 2008, and in revised form June 11, 2008.
Accepted for publication June 11, 2008.
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 2, pp. 562–567, 2008
Copyright Ó 2008 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/08/$–see front matter