In vitro and in vivo study on the antioxidant activity of dexrazoxane.

Abstract

The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in vitro and in vivo antioxidant effects of dexrazoxane.
The in vitro antioxidant activity of dexrazoxane as its total oxyradical scavenging capacity (TOSC) was assessed and compared to that of some classic antioxidants such as reduced glutathione (GSH), uric acid and trolox. The plasma antioxidant activity of 20 newly-diagnosed non-Hodgkin lymphoma (NHL) patients scheduled to receive anthracycline-containing chemotherapy (ProMECE-CytaBOM) was also evaluated. Results were expressed as TOSC units.
Dexrazoxane exhibited an in vitro scavenging capacity towards hydroxyl radicals 320% higher than that of GSH (p<0.00001), 20% higher than that of uric acid (p<0.001), and 100% higher than that of trolox (p<0.001). In the clinical study, ProMECE-CytaBOM infusion significantly reduced plasma TOSC in NHL patients (p=0.0001). Dexrazoxane supplementation was able to restore plasma antioxidant activity in two hours from the end of the ProMECE-CytaBOM infusion.
Dexrazoxane has in vitro antioxidant capacity. In vivo, it is able to reduce the epirubicin-induced free radical production. The intrinsic antioxidant effect of this compound could explain the reduction of the anthracyclines-induced toxicity in those patients treated with dexrazoxane supplementation.

Full text

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Original article
In vitro and in vivo study on the antioxidant activity of dexrazoxane
Fabio Galettaa, Ferdinando Franzonia, Giulia Cervettib, Francesco Regolid, Poupak Fallahia,
Leonardo Tocchinia, Angelo Carpic,*, Alessandro Antonellia, Mario Petrinib, Gino Santoroa
aDepartment of Internal Medicine, Italy
bDepartment of Oncology, Transplants and New Technologies in Medicine, Italy
cDepartment of Reproduction and Ageing, University of Pisa, Via Roma, 67, 56126 Pisa, Italy
dInstitute of Biology and Genetics, University of Ancona, Ancona, Italy
1. Introduction
Anthracyclines are widely used in the treatment of various
tumors such as aggressive lymphomas, but their utilization is
limited by acute (nausea, vomiting, mucositis, alopecia and
myelosuppression) [1] and chronic toxicity (cumulative cardiac
damage) [2–4]. There has been mounting evidence that the toxic
sideeffectsofanthracyclinesareatleastpartlycausedbyfreeradical
damage [5]. The toxicity of these compounds is thought to result
fromthe generation ofreactive oxygen species (ROS).Lebrechtetal.
demonstrated that anthracyclines induce heart-specific mutations
and quantitative defects in mitochondrial DNA [6]. These effects
result in an impairment of mitochondrial DNA-encoded respiratory
chain subunits and consequent respiratory chain dysfunction.
Defects in the respiratory chain promote the liberation of ROS that
cause site-specific damage to cell membranes [7,8].
Various approaches have been attempted to improve anthra-
cyclines therapeutic index and to reduce their citotoxicity, such as
the use of those anthracyclines with reduced cardiotoxicity (i.e.
epirubicin and mitoxantrone) or of drugs that showed potential
cardioprotective action.
The iron chelator dexrazoxane (Cardioxane1) is a cardiopro-
tective agent with proven efficacy in cancer patients receiving
anthracycline chemotherapy [9]. The co-administration of dexra-
zoxane with each dose of anthracycline has been shown to
significantly reduce cardiotoxicity in several randomized con-
trolled studies [10–17]. It is thought to reduce cardiac toxicity by
binding to free and bound iron, thus reducing the formation of
anthracycline-iron complexes and the generation of free radicals,
which are toxic to cardiac tissue [8].
Aim of the present study was to assess the effect of epirubicin-
based chemotherapy on the plasma antioxidant activity of never
treated Non-Hodgkin Lymphoma (NHL) patients and its modula-
tion by dexrazoxane supplementation.
2. Material and methods
Twenty patients inferior or equal to 60 years of age with newly-
diagnosed NHL, scheduled to receive the anthracycline-containing
Biomedicine & Pharmacotherapy 64 (2010) 259–263
A R T I C L E I N F O
Article history:
Received 19 November 2008
Accepted 7 June 2009
Available online 24 October 2009
Keywords:
Dexrazoxane
Free radicals
Antioxidants
Anthracyclines
Epirubicin
A B S T R A C T
Objectives: The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced
cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in
vitro and in vivo antioxidant effects of dexrazoxane.
Methods: The in vitro antioxidant activity of dexrazoxane as its total oxyradical scavenging capacity
(TOSC) was assessed and compared to that of some classic antioxidants such as reduced glutathione
(GSH), uric acid and trolox. The plasma antioxidant activity of 20 newly-diagnosed non-Hodgkin
lymphoma (NHL) patients scheduled to receive anthracycline-containing chemotherapy (ProMECE-
CytaBOM) was also evaluated. Results were expressed as TOSC units.
Results: Dexrazoxane exhibited an in vitro scavenging capacity towards hydroxyl radicals 320% higher
than thatof GSH(p < 0.00001), 20% higher than that ofuric acid(p < 0.001),and 100% higherthanthat of
trolox (p < 0.001). In the clinical study, ProMECE-CytaBOM infusion significantly reduced plasma TOSC
in NHL patients (p = 0.0001). Dexrazoxane supplementation was able to restore plasma antioxidant
activity in two hours from the end of the ProMECE-CytaBOM infusion.
Conclusions: Dexrazoxane has in vitro antioxidant capacity. In vivo, it is able to reduce the epirubicin-
induced free radical production. The intrinsic antioxidant effect of this compound could explain the
reduction of the anthracyclines-induced toxicity in those patients treated with dexrazoxane
supplementation.
? 2009 Elsevier Masson SAS. All rights reserved.
* Corresponding author. Tel.: +39 050 992955; fax: +39 050 992955.
E-mail address: a.carpi@med.unipi.it (A. Carpi).
0753-3322/$ – see front matter ? 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.biopha.2009.06.018

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chemotherapy ProMECE-CytaBOM, were studied. Included sub-
jects had an adequate performance status (score of 0 to 3 according
to the criteria of the Eastern Cooperative Oncology Group (ECOG))
[18]. We excluded patients who had active cardiac disease,
including myocardial infarction occurring within 12 months,
active angina pectoris, symptomatic valvular heart disease, or
uncontrolled congestive heart failure. The baseline resting left
ventricular ejection fraction had to be greater than or equal to 50%.
Moreover patients were excluded if they had abnormal findings at
physical examination, smoking habits, diabetes mellitus, or
received any drug treatment within the previous three months.
Clinical characteristics of the study populations are presented in
Table 1.
The ProMECE-CytaBOM regimen consisted of intravenous
epirubicin (a bolus dose of 40 mg/m2), followed by intravenous
cyclophosphamide (650 mg/m2)
(120 mg/m2) on day 1, and intravenous prednisolone (60 mg/
m2) on days 1–14. Vincristine (1.4 mg/m2, maximum 2), metho-
trexate (120 mg/m2), aracytin (300 mg/m2) and bleomicin (5 mg/
m2) were given intravenously on day 8. The cycle was repeated
every 3 weeks.
The patients were randomly assigned in two groups (n = 10) to
receive or not dexrazoxane hydrochloride (ICRF-187, Chiron,
Amsterdam, The Netherlands), given intravenously (400 mg/m2)
over 15 minutes, immediately after the cyclophosphamide-epir-
ubicin infusion.
All regimens were given via a peripheral vein. ProMECE-
CytaBOM was infused first, followed by dexrazoxane. No addi-
tional infusion was given. The chemotherapy was repeated on the
22ndday.TheethicalCommitteeoftheUniversityofPisaapproved
the study and a written consent was obtained from each patient.
and intravenous etoposide
2.1. Total Oxyradical Scavenging Capacity (TOSC) Assay
The assay allows to discriminate the relative antioxidant
capacity of a test compound by measuring the amount of ethylene
produced during the oxidation of alpha-keto-gamma-methiolbu-
tyricacid(KMBA,Sigma,0.2 mM)byhydroxyl,peroxylradicalsand
peroxynitrite [19]. As described in more detail [20], hydroxyl
radicals were generated at 35 8C by the iron plus ascorbate-driven
Fenton reaction (1.8 mM Fe3+, 3.6 mM EDTA, and 180 mM ascorbic
acid in 100 mM potassium phosphate buffer, pH 7.4). Peroxyl
radicals derived from thermal homolysis of 20 mM 2,20-azo-bis-
amidinopropane (ABAP, Sigma) at 35 8C in 100 mM potassium
phosphate buffer, pH 7.4. Peroxynitrite was generated from the
decomposition of N-ethylcarbamide (SIN-1, Sigma) in the presence
of0.2 mMKMBA,100 mMpotassiumphosphatebuffer,pH7.4,and
0.1 mM DTPA, at 35 8C. The concentration of SIN-1 was varied to
achieve an ethylene yield equivalent to the iron–ascorbate and
ABAP systems. Reactions with KMBA were carried out in 10 ml
vials sealed with gas-tight Mininert1valves (Supelco) in a final
volume of 1 ml. Ethylene production was measured by gas-
chromatographic analysis of 200 ml aliquots taken from the head
space of vials at timed intervals during the course of the reaction.
Analyses were performed with a Hewlett-Packard gas chromato-
graph (HP 6890 Series) equipped with a Supelco SPB-1 capillary
column and a flame ionization detector (FID). The oven, injection
and FID temperatures were, respectively, 35, 160 and 220 8C.
Helium was the carrier gas (at a flow rate of 1 ml/min) at a split
ratio of 20:1. Data were expressed as area under the kinetic curve
(trapezoid method). The within- and between-assay variability
was 2 and 4%, respectively.
2.2. Effect of dexrazoxane on in vitro TOSC
Dexrazoxane hydrochloride was obtained from Chiron as a
lyophilized powder in 500-mg vials. It was reconstituted in 25 ml
sterile water and then diluted in 25 ml of 100 mM potassium
phosphate buffer, pH 7.0, and centrifuged at 14,000 ? g for 30 min.
In vitro TOSC was evaluated in presence of vehicle or increasing
concentrations (10?7–10?3M) ofdexrazoxane added to the system
according to the above-described procedure. The linearity of dose-
response curve between dexrazoxane (in mg) and the antioxidant
(TOSC value) response was tested and good correlation coefficients
(generally greater than 0.9) were obtained at the different doses
used to test the validity of our experiments (Fig. 1). The results
obtained were expressed in TOSC units, and compared with the
specific TOSC of three classic antioxidants, eg. GSH, uric acid and
trolox (the water-soluble analogue of vitamin E).
2.3. Effect of ProMECE-CytaBOM treatment and dexrazoxane
supplementation on plasma TOSC
Plasma samples for evaluating TOSC were collected as follows:
at 7 a.m. on the morning of the first treatment and then 2,3, and
4 hours after the beginning of the first ProMECE-CytaBOM
treatment. Twenty millimeter of venous blood was drawn from
antecubital vein into Vacutainer tubes containing ethylenediami-
netetra-acetic acid (EDTA). The samples were immediately
protected from light and transported in ice to the laboratory,
where plasma was separated by a centrifuge. Plasma samples were
stored at ?80 8C in CO2 atmosphere for analysis within three
months. Altogether 80 plasma samples were forwarded for further
determination of TOSCA.
Table 1
Patients and lymphoma characteristics.
Age (years)
Sex (M/F)
LDH (U/l)
Histology
DLCL
Anaplastic CD30+
IPI
0–2
>2
Stage
II
III
IV
Response rate (%)
Complete response
Partial response
Failure free survival (months)
54?7
11/9
642?146
18
2
17
3
11
6
3
87
13
28?11
DLCL: diffuse large cell lymphoma; IPI: international
prognostic index.
Fig. 1. Dose-response curve of dexrazoxane (in mg) as anti-peroxyl (ROO?), anti-
hydroxyl (HO?), and anti-peroxynitrite radical antioxidant capacity.
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2.4. Statistical analysis
All data were expressed as mean ? standard deviation (SD). We
performed statistical analysis using one-way analysis of variance
(ANOVA), and two-way ANOVA, when required; linear correlation
analysis was used to assess relationships between variables.
Differences were considered significant when p < 0.05. All statistical
procedures and curve fitting for linear regression analysis were
performed by means of personal computer using the StatView
program (Abacus Concepts, Inc., version 4.57).
3. Results
3.1. Effect of dexrazoxane on in vitro TOSC
Fig. 2 shows the specific TOSC values of dexrazoxane towards
peroxyl radicals, hydroxyl radicals, and the peroxynitrite radicals
as compared with that of GSH, uric acid and trolox, respectively.
Dexrazoxane showed a good efficiency as scavenger of peroxyl
radicals exhibiting a TOSC value significantly higher (> 50%,
p < 0.001) than that of GSH, while it showed an antioxidant
activity lower than that obtained with uric acid and trolox
(p < 0.0001 for both). As scavenger of peroxynitrite free radicals,
dexrazoxane showed an antioxidant capacity 50% higher than that
of GSH (p < 0.001) and comparable to that of trolox and uric acid.
Of interest, the scavenging capacity of dexrazoxane towards
hydroxyl radicals was 320% higher (p < 0.00001) than that of GSH,
20% higher than that of uric acid, and 100% higher than that of
trolox (p < 0.001).
3.2. Effect of ProMECE-CytaBOM treatment and dexrazoxane
supplementation on plasma TOSC
Plasma antioxidant activity and its changes during chemother-
apy are presented in Fig. 3. Two hours after the beginning of the
first ProMECE-CytaBOM infusion, plasma TOSC towards the
hydroxyl radicals, peroxyl radicals and radicals derived from
peroxynitrite was significantly reduced in the both groups of
patients (p = 0.0001). One hour after the end of the ProMECE-
CytaBOM infusion (3 hours after the beginning of the infusion),
plasma antioxidant activity as TOSC values against all the three
Fig. 2. Antiperoxyl (top, ROO?), antihydroxyl (middle, HO?), and antiperoxynitrite
radicals (bottom,ONOO?) antioxidant capacity ofdexrazoxane, GSH, trolox,and uric
acid. *: p < 0.001 vs GSH, y: p < 0.0001 vs GSH, #: p < 0.00001 vs GSH, §: p < 0.01 vs
GSH, 8: p < 0.001 vs trolox and uric acid, ?: p < 0.01 vs trolox.
Fig. 3. Plasma anti-peroxyl (ROO?), anti-hydroxyl (HO?), and anti-peroxynitrite
radicals (ONOO?) antioxidant capacity at baseline, after epirubicin infusion
(2 hours) and aftersupplementation
dexrazoxane (3 hours) in non-Hodgkin lymphoma patients. *p < 0.001.
(groupA) ornot(groupB) with
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tested ROS increased in the both groups of patients, but, the group
treated with dexrazoxane supplementation showed a more
significant and rapid increase, as compared to the patients without
dexrazoxane (p < 0.0001). Four hours after the beginning of the
chemotherapy infusion, TOSC values towards hydroxyl, peroxyl
and nitroxide radicals were more increased in the dexrazoxane
group than in the group of patients without dexrazoxane
(p < 0.0001). Dexrazoxane was able to restore plasma antioxidant
activity in two hours from the end of the ProMECE-CytaBOM
infusion.
4. Discussion
The results of the present study are the following: first,
epirubicin-basedchemotherapy
activity in NHL patients; second, dexrazoxane has in vitro intrinsic
antioxidant activity; third, the dexrazoxane supplementation
improves plasma antioxidant activity of NHL patients treated
with epirubicin-based chemotherapy.
Toourknowledgethisisthefirstclinicalstudyassessinghuman
plasma antioxidant capacity during chemotherapy. The present
data clearly support the hypothesis that plasma scavenging
capacity is reduced during anthracyclines-based chemotherapy
against lymphomas. Our data showed that ProMECE-CytaBOM
infusion lowers the plasma antioxidant activity in NHL patients of
40%, thus confirming previous findings on the induction of
oxidative stress by anthracyclines [6]. In particular anthracyclines
induce defects inthe respiratory chain,that promote the formation
and liberation of reactive oxygen species [6]. In fact, the iron-
overload of cardiomyocytes determines the loss of functional Na+
channels; enhanced Na+channel inactivation causes the reduction
in the overshoot of cardiac action potential. These effects together
with a heterogeneous pattern of iron deposition, may enhance the
inhomogeneity of ventricular recovery times and increase the
arrhythmic risk [21,22]. Previously, we demonstrated that
dexrazoxane supplementation can prevent the increased disper-
sion of the QT interval induced by anthracyclines treatment, thus
showing clinically the cardiac protection by dexrazoxane [22].
Basser et al. demonstrated that anthracyclines such as
epirubicin, doxorubicin or daunorubicin are powerful inducers
of free radical species by generating oxygen radical either directly
after formation of complexes with ferric iron [23]. Iron can then,
after undergoingfurther internal redox
electrons to molecular oxygen thereby facilitating the formation
of highly cytotoxic hydroxyl radicals [24].
In the present study, we then demonstrated that those patients
treated with dexrazoxane supplementation showed a more rapid
restore of the basal plasma antioxidant activity than untreated
patients. This is the first direct observation of the in vivo
antioxidant effect of dexrazoxane. Previously, Hasinoff showed
that dexrazoxane exerts protective effects by quickly and
completely binding ferric and ferrous iron, even by displacing
the metal from complexes with anthracyclines [25]. Our results
showed that not only dexrazoxane effectively inhibits iron/
anthracycline-induced toxicity by preventing the formation of
toxic radicals, but also reduces anthracycline toxicity by a
mechanism independent from iron complexation. This is also
suggested by the results of the in vitro study showing that
dexrazoxane has potent intrinsic scavenging activity not only
against hydroxyl radicals, the typical free radical product of the
redox reaction of iron complexes, but also against peroxyl radicals
and nitrogen radicals, as compared to some classic antioxidants as
GSH, trolox and uric acid. In vivo the dexrazoxane is thought to
reduce the toxic effects of anthracyclines by binding to free and
bound iron, thereby reducing the formation of anthracycline-iron
complexes and the subsequent generation of reactive oxygen
reducesplasma antioxidant
reactions, transfer
species, which are toxic to surrounding cardiac tissue [26,27].
Moreover, Marty et al. [26] showed that dexrazoxane significantly
reduces the occurrence and severity of anthracycline-induced
cardiotoxicity in patients at increased risk of cardiac dysfunction
due to previous anthracycline treatment, without compromising
the antitumor efficacy of the chemotherapeutic regimen. In fact,
when given in combination with anthracyclines (e.g. doxorubicin
orepirubicin)thepharmacokineticsofdexrazoxaneareunchanged
[28]. Additional studies of anthracycline metabolism when given
in combination with dexrazoxane, both in single arm and
randomized crossover studies, have generally shown no change
in anthracycline metabolism or clearance. There is no pharmaco-
kinetic interaction of dexrazoxane on anthracycline metabolism
and, therefore, pharmacokinetics cannot account for the cardio-
protective effects described for dexrazoxane.
The finding that dexrazoxane has anti-hydroxyl radicals, anti-
peroxyl radicals and anti-peroxynitrite radicals antioxidant
activity is especially relevant in view of recent information
indicating that relatively ‘pure’ antioxidants - such as vitamin E
(anti-peroxyl) and ascorbic acid (anti-hydroxyl) - can be converted
intopro-oxidantmolecules[29],andtheoretically,thismakestheir
combined activities necessary to obtain a net antioxidant effect
[30].
The major ROS implicated in the pathological processes are
superoxide anion (ROO?), hydrogen peroxide (H2O2), hydroxyl
radical (HO?), and the reactive nitrogen species, nitric oxide (NO)
and peroxynitrite (HOONO?). Although all oxyradicals are poten-
tially toxic, their chemical reactivity towards biological targets is
different; accordingly, the relative efficiency of an antioxidant can
vary depending on the oxidant [31]. With regard to this, the TOSC
assay has been standardized for measuring the total antioxidant
scavenging activity towards various radicals, i.e. peroxyl radicals,
hydroxyl radicals and free radicals deriving from the decomposi-
tion of peroxynitrite [19].
In conclusion, this study demonstrated that the dexrazoxane
has intrinsic antioxidant activity, either in vitro or in vivo. This
effect could justify the reduction of the toxicity of anthracycline
therapy after supplementation with dexrazoxane.
5. Conflicts of interest
None.
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