Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem Toxicol
Cisplatin (cis-diamminedichloroplatinum (II)) is an effective agent against various solid tumours. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.g. carboplatin, oxaliplatin, nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the effectiveness and to lessen the toxicity of cisplatin. Several agents have been tested to see whether they could ameliorate or augment the nephrotoxicity of platinum drugs. This review summarizes these studies and the possible mechanisms of actions of these agents. The agents that have been shown to ameliorate experimental cisplatin nephrotoxicity include antioxidants (e.g. melatonin, vitamin E, selenium, and many others), modulators of nitric oxide (e.g. zinc histidine complex), agents interfering with metabolic pathways of cisplatin (e.g. procaine HCL), diuretics (e.g. furosemide and mannitol), and cytoprotective and antiapoptotic agents (e.g. amifostine and erythropoietin). Only few of these agents have been tested in humans. Those agents that have been shown to augment cisplatin nephrotoxicity include nitric oxide synthase inhibitors, spironolactone, gemcitabine and others. Combining these agents with cisplatin should be avoided.
Agents ameliorating or augmenting the nephrotoxicity of cisplatin
and other platinum compounds: A review of some recent research
Badreldin H. Ali
, Mansour S. Al Moundhri
Department of Pharmacology and Clinical Pharmacy, College of Medicine, Sultan Qaboos University, P.O. Box 35, Al-Khod, Muscat 123, Oman
Department of Medicine, College of Medicine, Sultan Qaboos University, P.O. Box 35, Al-Khod, Muscat 123, Oman
Received 21 November 2005; accepted 29 January 2006
Cisplatin (cis-diamminedichloroplatinum (II)) is an eﬀective agent against various solid tumours. Despite its eﬀectiveness, the dose of
cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.g. carboplatin, oxaliplatin,
nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the eﬀectiveness and to
lessen the toxicity of cisplatin. Several agents have been tested to see whether they could ameliorate or augment the nephrotoxicity of
platinum drugs. This review summarizes these studies and the possible mechanisms of actions of these agents. The agents that have been
shown to ameliorate experimental cisplatin nephrotoxicity include antioxidants (e.g. melatonin, vitamin E, selenium, and many others),
modulators of nitric oxide (e.g. zinc histidine complex), agents interfering with metabolic pathways of cisplatin (e.g. procaine HCL),
diuretics (e.g. furosemide and mannitol), and cytoprotective and antiapoptotic agents (e.g. amifostine and erythropoietin). Only few
of these agents have been tested in humans. Those agents that have been shown to augment cisplatin nephrotoxicity include nitric oxide
synthase inhibitors, spironolactone, gemcitabine and others. Combining these agents with cisplatin should be avoided.
2006 Elsevier Ltd. All rights reserved.
Keywords: Cisplatin; Nedaplatin; Lipoplatin; Carboplatin; Oxaliplatin; Nephrotoxicity
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
2. Agents that ameliorate the nephrotoxicity of platinum drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
2.1. Antioxidant and antilipid peroxidation agents.................................................... 1175
2.2. Modulators of nitric oxide .................................................................. 1177
2.3. Diuretics and hydration .................................................................... 1177
2.4. Agents interfering with metabolic pathways of cisplatin . . .......................................... 1177
2.5. Modulators of adenosine ................................................................... 1178
2.6. Tissue cytoprotectors ...................................................................... 1178
2.7. Other protective agents .................................................................... 1179
3. Agents that augment the nephrotoxicity of platinum drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
3.1. Inhibitors of renal excretion ................................................................. 1179
3.2. Agents that enhance lipid peroxidation ......................................................... 1180
3.3. Modulators of nitric oxide (NO) ............................................................. 1180
3.4. Others ................................................................................. 1180
0278-6915/$ - see front matter 2006 Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +968 2441 5160; fax: +968 2441 5107.
E-mail address: email@example.com (B.H. Ali).
Food and Chemical Toxicology 44 (2006) 1173–1183
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
1. Intr oduction
Cisplatin (cis-diamminedichloroplatinum (II)) is a
water-soluble planar member of the platinum coordination
complex class of anticancer drugs (Fig. 1a). It is an organic
complex formed by an atom of platinum surrounded by
chloride and ammonium atoms in the cis position of a hor-
Cisplatin and other related drugs (e.g. carboplatin, see
Fig. 1b) form strong electrophilic intermediates that act
via nucleophilic substitution reactions to form inter- and
intra-strand DNA cross-links. Cisplatin remai ns a major
antineoplastic drug for the treatment of solid tumours such
as metastatic bladder, testicular and ovarian carcinomas
(Taguchi et al., 2005). It is given either intravenously or
intraperitoneally, binds to serum protein by about 90%,
distributes to most tissues and is cleared in unchanged form
by the kidney (Royer et al., 2005).
The mechanism of action of cisplatin involves entering
the cell, where Cl
dissociates leaving a reactive complex
that reacts with water and then interacts with DNA. It
causes intrastrand cross-linking, probably be tween N7
and O6 of the adjacent guanine molecules, which results
in local denaturation of the DNA chain. Cisplatin also
damages cell mitochondria, arrests cell cycle in the G2
phase, inhibits ATPase activity, alters the cellular transport
system, and eventually causing apoptosis, inﬂammation,
necrosis and death in cells (Boulikas and Vougiouka,
2003; Jo et al., 2005; Taguchi et al., 2005). Enhanced
tumour necrosis factor-a (TNFa) production has been sug-
gested to mediate, in part, cisplatin nephrotoxicity
(Ramesh and Reeves, 2004). Light and electron microscopy
have shown that the cisplatin-induced injury and necrosis
in the rat kidney are predominantly localized in the S3 seg-
ment of proximal tubules in the corticomedullary region,
with or without accompanying distal changes (Townsend
et al., 2003). Cisplatin has a synergistic cytotoxic action
with radiation and other chemotherapeutic agents . The
major limitation in the clinical applications of cisplatin
has been the development of cisplatin resistance by
tumours (Boulikas and Vougiouka, 2003).
A recent study showed that kidney tissue accumulation
of cisplatin administered at 3.75 mg/kg was similar to that
of the newer analogue nedaplatin administered at 24 mg/kg
(Kawai et al., 2005), and that both drugs at these two doses
induced similar eﬀects on the kidney. It was inferred, there-
fore, that nedaplatin less frequently causes renal toxicity in
comparison to cisplatin due to lower kidney accumulation.
In another recent work, Uehara et al. (2005) compared the
nephrotoxicity of cisplatin (7.5 mg/kg) to that of the sec-
ond-generation platinum complex nedaplatin (15 mg/kg)
in rats, and reported that nedaplatin is less nephrotoxic
than cisplatin. The nephrotoxicity of the newer drug was
only evident in the older rats, and that the lesions it
induced were milder and morphologically diﬀerent from
those induced by cisplatin. In patients with advanced
non-small-cell lung cancer, Rosell et al. (2002) compared
paclitaxel/carboplatin with paclitaxel/cisplatin, and found
that although paclitaxel/carboplatin yielded a similar
response rate, the signiﬁcantly longer median survival
obtained with pa clitaxel/cisplatin indicates that cisplatin-
based chemotherapy should be the ﬁrst treatment option.
The toxic eﬀects of the drug in man and animals include
nephrotoxicity, ototoxicity, neurotoxicity and bone mar-
row suppression, but its chief dose-limiting side eﬀect is
nephrotoxicity (Sastry and Kellie, 2005; Arany and Saﬁr-
stein, 2003; Boulikas and Vougiouka, 2003). About 20%
of acute renal failure cases among hospitalized patients
are due to cisplatin nephrotoxicity (Berns and Ford,
1997). Despite intensive prophylactic measures, irreversible
renal damage occurs in about one-third of cisplatin-treated
patients (Santoso et al., 2003; Taguchi et al., 2005).
The kidney selectively accumulates cisplatin and its ana-
logues to a higher degree than other organs, probably
through mediated transport (Arany and Saﬁrstein, 2003;
Kawai et al., 2005 ). Functionally, the nephrotoxicity causes
reduced renal perfusion and a concentrating defect, and
changes in renal haemodynamics (including a decrease in
Fig. 1a. The structure of cisplatin.
Fig. 1b. The structure of carboplatin.
1174 B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183
the kidney nitric oxide level). Morphologically, the nephro-
toxicity induces necrosis of the terminal portion of the
proximal tubule and apoptosis, predominantly in cells in
the distal nephron. Cisplatin treatment also induces exten-
sive death of cells in the proximal and distal tubules and
loop of Henle (Arany et al., 2004; Taguchi et al., 2005).
Cisplatin nephrotoxicity has been demonstrated to be
mediated by DNAase1 (Basnakian et al., 2005). This
enzyme is a highly active renal endonuclease, and its silenc-
ing by antisense is cytoprotective against the in vitro
hypoxia injury of the kidney tubular epithelial cells (Basn a-
kian et al., 2005). The nephrotoxicity of cisplatin is due to a
complex metabolic pathway that activates the drug to a
potent kidney toxin.
Among the earliest reactions of the kidney to cisplatin is
the activation of the mitogen-activated protein kinase
(MAPK) cascade (which is involved in the action of most
non-nuclear oncogenes, and is responsible for cell response
to growth factors), and molecular responses typical of the
stress response (Arany and Saﬁrstein, 2003). Repression
of genes characteristic of the mature phenotype of the
kidney, especially those serving transport function of the
kidney, is also prominent. Metabolic responses, cell cycle
events and the inﬂammatory cascade seem to be important
determinants of the degree of renal failure induced by cis-
platin (Arany and Saﬁrstein, 2003).
Several strategies have been explored to reduce the side
eﬀects of cisplatin therapy, including the use of less inten-
sive treatment, replacement of the nephro- and neurotoxic
cisplatin by its less toxic analogue carboplatin. The latter
drug generates a reactive species much more slowly than
cisplatin. Therefore, its pharmacokinetic and toxicological
characteristics are diﬀerent (Taguchi et al., 2005).
Several general, pathological and molecular aspects of
the nephrotoxicity of cisplatin have been reviewed before
(e.g. Madias and Harrington, 1978; Daugaard, 1990;
Anand and Bashey, 1993; Boulikas and Vougiouka, 2003;
Arany and Saﬁrstein, 2003; Taguchi et al., 2005). A
detailed and comprehensive review of all aspects of cis-
platin-induced nephrotoxicity is beyond the scope of this
article. In the present review, the aim was to brieﬂy summa-
rize some of the more recent reports on the agents that
have been reported to either ameliorate or augment the
nephrotoxicity of cisplatin and other platinum analogues.
2. Agen ts that ameliorate the nephrotoxicity of platinum
The agents discussed below are summarized in Table 1.
2.1. Antioxidant and antilipid peroxidation agents
It has been established that cisplatin and other platinum
agents inter act with thiol groups and macromolecules
(Matsushima et al., 1998; Baliga et al., 1999). The nephro-
toxicity of these drugs is closely related to the activity of
A list of some agents reported to ameliorate the nephrotoxicity of cisplatin
Agent Dose, route and duration Species Reference
Hyperbaric oxygen 2.5 · atmospheric pressure, 1 h/day, 7 days Rats Atasoyu et al. (2005)
Xanthorrhizol 200 mg/kg/day, p.o., 4 days Rats Kim et al. (2005)
Lycopene 4 mg/kg, p.o., 10 days Rats Atessahin et al. (2005)
Vitamin C or E 100 mg/kg, i.p., once Rats Kadikoylu et al. (2004)
Tomato juice + dried black grapes Supplement to diet, 6 days Rats Cetin et al. (2006)
Capsaicin 10 mg/kg/day, p.o., 6 days Rats Shimeda et al. (2005)
Vitamin E 1.5 mg/kg, i.p., 5 days Rats Naziroglu et al. (2004)
Quercitin 50 mg/kg, p.o., up to 20 days Rats Francescato et al. (2004)
Caﬀeic acid 10 lg/kg, i.p., 5 days Rats Ozen et al. (2004)
Desferrioxamine 250 mg/kg, i.p., once Rats Kadikoylu et al. (2004)
Edarabone 1 or 5 mg/kg, i.v., once Rats Satoh et al. (2003)
Glutamine 300 mg/kg, p.o., once Rats Mora et al. (2003)
Gum Arabic 7.5 g/kg, p.o., Rats Al-Majed et al. (2003)
Rebamipide 140 mg/kg, i.p., 7 days Rats Saad et al. (2001)
L-arginine 300 mg/kg, i.p., 6 days Rats Saleh and El-Demerdash (2005)
Amifostine 910 mg/m
by infusion (repeated at
3 week interval)
Humans Hartmann et al. (2000)
Bismuth subnitrate 100 mg/kg, p.o., 5 days Mice Kondo et al. (2004)
Salicylate 100 mg/kg (bid), s.c., 3 days Mice Ramesh and Reeves (2004)
100 mg/kg (bid), i.v., 5 days Rats Li et al. (2002)
Procaine HCl 200 mg/kg, i.p., once Rats Fenoglio et al. (2002)
Serum thymic factor 200 lg/kg/day, i.v., 2 days Rats Kohda et al. (2005)
B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183 1175
reactive oxygen specie s (ROS). The latter include superoxide
anion radical, hydrogen radical, hydrogen peroxide, singlet
oxygen, and nitric oxide (see below), and these are directly
involved in oxidative damage of cellular macromolecules
such as lipids, proteins and nucleic acids in tissues (Sogut
et al., 2004). Many proteins (e.g. metallothioinine) an d small
molecules (glutathione, GSH) are involved in the metabo-
lism of these agents. Platinum complexes are very reactive
towards the cysteine residue of GSH, which detoxi ﬁes these
compounds by a rapid binding mechanism (Jansen et al.,
2002). The site and source of ROM are not well deﬁned,
and cytochrome P 450 2E1 has been suggested to be involved
in the generation of ROM that causes cisplatin nephrotoxi-
city and initiates apoptosis (Liu and Baliga, 2003). Identiﬁ-
cation and localization of speciﬁc CYP isoenzymes in
human renal tubular cells, and the development of speciﬁc
inhibitors may aid in either the prevention or amelioration
of cisplatin nep hrotoxicity.
Cetin et al. (2006) have recently reported that cisplatin
treatment causes signiﬁcant oxidant loading to the kidney
through both xanthine oxidase activation and impaired
antioxidant defense system, which resulted in a ccelerated
oxidation reactions in the kidney tissues.
The antioxidant agents that have been reported to either
ameliorate or prevent the nephrotoxicity of these drugs
include melatonin (Hara et al., 2001; Sener et al., 2000;
Saad and Al-Rikabi, 2002), selenium (Hu et al., 1997; Cam-
argo et al., 2001), vitamin E (Naziroglu et al., 2004), N-ace-
tylcysteine (Wu et al., 2005) and many others.
Among the antioxidants that have been tried against
nephrotoxicity of cisplatin are those that have been
extracted from natural products (mainly medicinal plants
and dietary components) (Conklin, 2004). It has been
shown by many workers that dietary antioxidants may
detoxify reactive oxygen species and may also enhance the
anticancer eﬀects of chemotherapy, and reduce some of
the side eﬀects (reviewed by Conklin, 2000). Certain side
eﬀects, however, such as alopecia and myelosuppression,
are not prevented by antioxidants, and agents that reduce
or prevent these side eﬀects may also interfere with the anti-
cancer eﬃcacy of chemotherapy (Conklin, 2000). An ethyl
acetate extract of a polypore fungus Phellinus rimosus has
been shown to protect mice against cisplatin nephrotoxicity
when the extract was given orally at doses of 25 and 50 mg/
kg (Ajith et al., 2002). The fungal extract probably exerted
its nephroprotecting action via enhancing the renal antiox-
idant system, and it did not interfere with the antitumour
activity of cisplatin. Shirwaikar et al. (2003, 2004a) reported
that treatment of rats with extract of the ﬂowers of the plant
Pongamia pinnata (300 and 600 mg/kg/ day for 10 days,
p.o.) or Aerva lanata (75, 150 and 300 mg/kg) ameliorated
the nephrotoxicity of cisplatin in a dose-dependent fashion.
The protection was ascribed to the fact that the extract con-
tains two ﬂavonoids with strong antioxidant activity,
namely kaempferol and 3,5,6,7,8-pentamethyoxyﬂavone.
In another experimen t, the antioxidant agent lupeol, iso-
lated from the medicinal plant Crataeva nurvala, and given
at oral doses of 40 and 50 mg/kg has been shown to mitigate
the nephrotoxicity of cisplatin in rats (Shirwaikar et al.,
2004b). More recently, Kim et al. (2005) studied the eﬀect
of xanthorrhizol (isolated from Curcuma xanthorrhiza)on
cisplatin-induced nephrotoxicity in mice. Oral pretreatment
with the extract (200 mg/kg/day for 4 days) signiﬁcantly
attenuated the histological and biochemical signs of neph-
rotoxicity. Xanthorrhizol nephroprotection was more eﬃ-
cacious than that of curcumin (Curcuma longa) given at
the same dosage. Recently, Shimeda et al. (2005) reported
that treatment of rats with capsaicin (the major pungent
ingredient in red hot pepper) at an oral dose of 10 mg/kg/
day for 6 days was eﬀective in protecting against cisplatin-
induced nephrotoxicity and increased lipid peroxidation.
It has been shown that the radical scavenging site of capsa-
icin is the C7-benzyl carbon, and that it inhibits the oxida-
tion almost as eﬀectively as alpha- tocopherol in liposomal
membranes (Shimeda et al., 2005). Other recent reports that
showed ameliorative eﬀects of antioxidant natural products
in cisplatin nephrotoxicity include root ethanol ic extract
from Cassia auriculata (600 mg/kg) (Annie et al., 2005)
and naringenin (20 mg/kg/day, 10 days) extracted from
grapefruit (Badary et al., 2005). The ﬂavonoid naringenin
has been shown to have strong in vitro and in vivo an tipro-
liferative and antioxidant actions (Totta et al., 2004). These
actions may be the basis of its protection against cisplatin
nephrotoxicity. It has also been shown that the nephropro-
tective action of naringenin is not mediated through reduc-
tion in the level or accumulation of platinum in the renal
tissues. Therefore, naringenin may not alter cisplatin bio-
availability, and hence may not aﬀect its levels in tumor
tissues (Badary et al., 2005).
There are reports in the literature of antioxidants that
were either only slightly eﬀective or ineﬀective in ameliorat-
ing or protecting against cisplatin nephrotoxicity. For
example, oral pretreatment with the natural antioxidant
curcumin (8 mg/kg, twice) before cisplatin treatment was
ineﬀective in protecting rats from the nephrotoxicity
(Antunes et al., 2001). The failure of curcumin in this
experiment could be ascribed to the low dose and short
duration of treatment. In order to obtain a palliative eﬀect
of curcumin against gentamicin nephrotoxicity, the former
was given at an oral dose of 200 mg/kg/day for 10 days (Ali
et al., 2005). Glutamine (300 mg/kg orally for up to 7 days)
partially protected rats against cisplatin-induced lipid
peroxidation damage, but it was not enough to inhibit
cisplatin-induced nephrotoxicity (Mora et al., 2003 ). In
another report, Al-Harbi et al. (1995) reported that treat-
ment of rats with the iron chelator desferrioxamine
(250 mg/kg, intraperitoneally) 30 min before cisplatin
administration did not protect the kidney from the damag-
ing eﬀects of the drug, and actually aggravated the nephro-
toxicity. Several other authors have reported diﬀerent
results. For example, Watanabe and Kanno (1998) indi-
cated that desferrioxamine pretreatment (100 mg/kg,
intraperitoneally) 60 min before cisplatin administration
prevented cisplatin-induced nephrotoxicity. Likewise,
1176 B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183
Ozdemir et al. (2002) reported that desferrioxamine pre-
treatment (100 mg/kg) 1 h before 0.9 mg/kg cisplatin was
safe, and was eﬀective in ameliorating histological and bio-
chemical signs of nephrotoxicity in mice. More recently
Kadikoylu et al. (2004) found a beneﬁcial eﬀect for desfer-
rioxamine against cisplatin nephrotoxicity in rats, although
it was suggested that vitamin C and vitamin E are more
eﬀective on antioxidant enzymes than desferrioxamine.
Al-Majed et al. (2003) reported that gum Arabic (7.5 mg/
kg/day for 5 days) did not aﬀect cisplatin-induced nephro-
toxicity in rats, although they claimed that it signiﬁcantly
reduced the cisplatin-induced lipid peroxidation. Al-Majed
et al. (2003) inferred that lipid peroxidation is not the main
cause of cisplatin nephrotoxicity. This is not in line with the
general consensus in the published literature, which indi-
cates that lipid peroxidation is responsible (see e.g. Satoh
et al., 2003; Shimeda et al., 2005). Moreover, it has been
shown that gum Arabic, at doses that bracket the dose used
by Al-Majed et al. (2003) does not have either an antioxi-
dant or antilipid peroxidation acti on (Ali, 2004).
A double-blind trial was conducted in 48 Dutch patients
with cancer and who received cisplatin-based chemother-
apy, in which half the patients were given a dietary supple-
ment that consisted of vitamin C, vitamin E and selenium.
The other half received a placebo. No signiﬁcant diﬀerences
were found between the two grou ps with respect to the
severity of the nephrotoxi city and ototoxicit y induced by
cisplatin (Weijl et al., 2004). The failure of the supplement
to ameliorate the toxic signs was ascribed to either poor
compliance of the patients or to inadequate supplementa-
tion. Higher doses were suggested for further investiga-
tions. It should be mentioned, however, that oral
supplementation of patients receiving cisplatin chemother-
apy with vitamin E (300 mg/d before cisplatin chemother-
apy and continued for 3 months after the suspension of
treatment) was eﬀective in decreasing the incidence and
severity of peripheral neurotoxicity (Pace et al., 2003).
2.2. Modulators of nitric oxide
NO plays an important role in maintaining normal renal
function (Fujihara et al., 2006; Saleh and El-Demerdash,
2005). The role, however, played by either NO or NO syn-
thase inhibitor in cisplatin nephrotoxicity is not clear. Sri-
vastava et al. (1995, 1996) were among the ﬁrst who
provided evidence for the involvement of NO in cisplatin-
nephrotoxicity. These workers have shown that the inhibi-
tor of NO synthase, NG-nitro-
L-arginine methyl ester, was
eﬀective in mitigating the lipid peroxidation and other
biochemical changes associated with nephrotoxicity caused
by the administration of cisplatin. Thi s was later conﬁrmed
by Saad et al. (2002), who investigated the eﬀect of an NO
synthase inhibitor, 2-amino-4-methylpyrid ine, on cisplatin-
induced nephrotoxi city in rats, an d reported an ameliora-
tion of this condition.
Nitric oxide (NO) is known to play a role in maintaining
normal renal function (see the review of Passauer et al.,
2005). Srivastava et al. (1995) tested zinc histidine complex
as a nephroprotectant against cisplatin nephrotoxicity, and
found that it was eﬀecti ve in ameliorating several clinical
and biochemical signs of toxicity in rats. Srivastava et al.
(1995) suggested that cisplatin might play a biochemical
role in arginine-metabolism, including nitric oxide (NO)
production. It was also reported that the decrease in the
kidney nitric oxide (NO) level contributes, at least in part,
to the mechanism underlying cisplatin nephrotoxicity. Saad
et al. (2002) reported that administration of the inhibitor of
the NO synthase inhibitor, 2-amino-4-methylpyridine, to
rats exacerbates cisplatin-induced nephrotoxicity.
L-arginine (a precursor of NO) has nephroprotective
eﬀects and might be useful in improving the therapeutic
index of cisplatin in rats. On the other hand an inhibitor
of nitric oxide synthase, L-NAME had the opposite eﬀect
(Saleh and El-Demerdash, 2005).
2.3. Diuretics and hydration
Both human and animal studies have shown that the use
of diuretics (e.g. furosemide, mannitol and others) and
hydration substantially mitigate cisplatin, carboplatin,
and ormaplatin nephrotoxicity (Cornelison and Reed,
1993; Yoshizawa et al., 1998; Santoso et al., 2003; Hanigan
et al., 2005).
In a randomized trial involving 49 women, Santoso et al.
(2003) showed that hydration with either saline or saline
and frusemide appears to be associated with less cisplatin
nephrotoxicity than saline and mannitol. The mechanism
by which salt loading protects the kidney from cisplatin-
induced nephrotoxicity is not clear. In a recent study by
Hanigan et al. (2005), the toxicity of cisplatin toward
LLC-PK (1) cells was found to vary dramatically according
to the tissue culture media used for 3 h cisplatin exposure.
Further experiments indicated that minor changes in
the sodium concentration among standard tissue culture
media modulated cisplatin nephrotoxicity. NaCl has been
shown to protect against cisplatin-induced nephrotoxicity
in vivo, but has never before been demonstrated in vitro.
NaCl did not alter the cellular accumulation of cisplatin.
NaCl altered the osmolarity of the external media, and its
eﬀect was replicated by substituting equiosmolar concentra-
tions of impermeant anions or cations. The change in osmo-
larity appeared to have triggered a stress response within
the cell that modulated sensitivity to cisplatin (Hanigan
et al., 2005). In contrast, a singl e report showed that cis-
platin nephrotoxicity in rabbits is aggravated by concomi-
tant treatment with Spironolactone (Ahmida et al., 2001).
2.4. Agents interfering with metabolic pathways
It has been shown that the local anaesthetic drug pro-
caine HCl increases the therapeutic index of cisplatin and
reduces its nephrotoxicity (Zhang and Lindup, 1997). The
mechanism of action of this protection has not been fully
B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183 1177
elucidated, but it has recently been shown by Fenoglio
et al. (2002) that nephroprotection of procaine HCl against
cisplatin may be related to its inﬂuence on some enzyme
activities involved in important renal metabolic pathways.
These authors have also reported that this nephroprotec-
tion is ascribed mainly to procaine HCl and not to its
metabolite para-aminobenzoic acid (PABA). More
recently, these authors have conﬁrmed the protective
action of procainamide HCl against the nephrotoxicity of
cisplatin given in small repeated doses in female rats (Feno-
glio et al., 2005). Previously, however, it has been shown
that treatment with PABA lowers the exposure of kidney
to platinum in mice (Esposito et al., 1993), and also pro-
tects against the oxidative stress and generation of lipid
peroxidation linked to cisplatin administration, without
reducing antitumour activity.
The class I antiarrhythmic drug procainamide (Pd) was
tested on BDF1 mice for its chemoprotective activity
against cisplatin toxicity without diminishing antitumour
activity (Esposito et al., 1996). Pd signiﬁcantly reduced
the general toxicity and lethality of cisplatin in mice. The
nephroprotection was ascribed to the formation of a less
toxic triamine platinum complex that contains procaine
as a ligand (Viale et al., 2000). In this regard, Pd was found
to be superior to the related drug, procaine HCl (which dif-
fers from Pd only in the replacement of the amide by an
It has recently been shown that the nephrotoxicity of
cisplatin can be blocked by inhibiting either of two enzymes
expressed in the proximal tubules, gamm a-glutamyl trans-
pepetidase (GGT) or cysteine-S-conjugate beta-lyase. These
data led Townsend et al. (2003) to hypothesize that the
nephrotoxicity of cisplatin is the result of metabolic activa-
tion of cisplatin in the kidney to a more potent toxin.
2.5. Modulators of adenosine
It is established that adenosine is involved in the regula-
tion of renal haemodynamics, tubular function, and
hormone release. In contrast to other vascular beds, aden-
osine induces vasoconstriction in renal vessels, thereby cou-
pling renal perfusion to the metabolic rate of the organ
(Benoehr et al., 2004). The concentration of adenosine in
the kidney has been reported to increase in drug-induced
nephrotoxicity, consecutively causing a decrease of GFR
(Heidemann et al., 1989; Knight et al., 1991; Bhat et al.,
2002). Theophylline (a non-selective adenosine receptor
antagonist) may act synergistically with cisplatin as an
antitumour agent (Gude et al., 2002), and there is a new
trend to use theop hylline as a prophylactic medication to
reduce the severi ty of renal dysfunction induced by neph ro-
toxic drugs (Vassallo and Lipsky, 1998; Bagshaw and
In rats, continuously applied treatment with aminophyl-
line (a non-selective adenosine receptor antagonist) given
at a dose of 24 mg/kg/12 h for 5 days, was able to prevent
the reduction of glomerular ﬁltration rate (GFR) induced
by cisplatin when it was given during the maintenance
phase of acute tubular necrosis, and it had no eﬀect when
only administered prophylactically before cisplatin nephro-
toxicity (Heidemann et al., 1989). On the other hand,
enprofylline (which is a xanthine derivative lacking adeno-
sine receptor antagonism) at a dose of 20 mg/4 h, had no
protective action against cisplatin nephrotoxicity. A diﬀer-
ent result was obtained by Saad et al. (2004), who reported
that rats treated with theophylline (0.8 mg/ml in the drink-
ing water for 2 weeks) together with cisplatin (7 days after
the start of theophylline treatment) showed extensive wide-
spread damage with intr atubular calciﬁcation. The methyl-
xanthine derivative pentoxifylline (50 mg/kg per day for
2 weeks), on the other hand, ameliorated the overt changes
induced by cisplatin treatment. It is well documented that
cisplatin treatment increases the expression of adenosine
A (1) receptors in both kidney and testes. However, the
eﬀect of adenosine at these recep tors is controversial.
Adenosine A (1) receptors have been documented to be
involved in either cytoprotection or aggravation of nephro-
toxicity (Saad et al., 2004).
Patients with cancer but with normal renal function usu-
ally suﬀer a decrease in GFR after a single cycle of cisplatin
chemotherapy, despite hydration and osmotic diuresis (e.g.
using mannitol). Benoehr et al. (2004) foun d that a loading
dose of theophylline (4 mg/kg, i.v. over 30 min before cis-
platin, followed by 0.4 mg/kg per min over a minimum of
6 h and then 350 mg three times orally for four consecutive
days) after completion of chemotherapy, was eﬀective in
preserving kidney function in terms of GFR.
2.6. Tissue cytoprotectors
The organic thiophosphate amifostine (Ethyol) is a
broad-spectrum cytoprotector of normal tissues that has
been approved by the US Food and Drug Administration
for use in patients receiving cisplatin. Such administration
of amifostine has been reported in most (e.g. Schuchter,
1996; Asna et al., 2005), but not all studies (Ramnath
et al., 1997; Gradishar et al., 2001) to mitigate cisplatin-
related toxicities. Recently, it has been shown that amifos-
tine does not protect against the ototoxicity of high-dose
cisplatin combined with etoposide and bleomycin in pediat-
ric germ-cell tumors (Marina et al., 2005). In a recent
study, Sastry and Kellie (2005) reported a case of severe
toxicity with cisplatin in a girl with epithelial cell carcinoma
of the ovary, despite the use of amifostine. In another
study, Planting et al. (1999) indicated that in patients with
advanced head and neck cancer, in combination with
weekly administered cisplatin, amifostine reduced the risk
of thrombocytopaenia, hypomagnesaemia as wel l as sub-
clinical neurotoxicity, but did not resul t in a higher dose
intensity of cisplatin. Addition of amifostine did not com-
promise the antitumour eﬀect of cisplatin. The preclinical
evaluation of amifostine conﬁrmed the selective protection
of normal tissues against toxicity due to cisplatin therapy,
while maintaining the antitumour eﬀects. The mechanism
1178 B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183
of protection involved selective uptake of the free thiol,
amifostine, into normal tissue compared with tumour tis-
sue, intracellular binding and therefore detoxiﬁcation of
anticancer drugs, as well as through the scavenging of oxy-
gen free radicals. Although vigorous hydration schedules
have helped to alleviate nephrotoxicity, ototoxicity and
cumulative dose-related peripheral ne uropathy, these side
eﬀects remain important dose-limiting toxicities related to
cisplatin therapy. The preclinical and clinical results to date
demonstrate that amifost ine can protect against cispl atin
toxicities, in particular nephrotoxicity. Recent studies have
demonstrated that higher single and cumulative cisplatin
doses have an important impact on survival outcome; how-
ever, the improvement in survival comes at the cost of
increased acute and cumulative haematological, renal and
neurological toxicities that can result in serious morbidity.
The role of amifostine as a supportive measure to reduce
these toxicities oﬀers the possibility of improving the qual-
ity of life of patients receiving chemotherapy (Schuchter,
Erythropoietin (EPO) has recently been shown to exert
important cytoprotective and antiapoptotic eﬀects in
experimental cisplatin-induced nephrotoxicity and ischae-
mic acute renal injury (Yalcin et al., 2003; Vesey et al.,
2004). The results suggest that, in addition to its well-
known erythropoietic eﬀects, EPO inhibits apoptotic cell
death, enhances tubular epithelial regeneration and pro-
motes renal functional recovery in hypoxic or ischaemic
acute renal injury. EPO was claimed to be as eﬀective as
amifostine (Yalcin et al., 2003).
Recently, a new chemoprotector, disodium-2,2
bis-ethane sulfonate (BN7787), against cisplatin nephro-
toxicity in humans ha s been investigated in 21 patients with
advanced solid tumors. The selective protective action of
this agent is suggested to arise from the preferential uptake
of the dru g in the kidneys, where BN7787 is intracellularly
converted into mesna (2-mercapto ethane sulfonate), which
in turn, can prevent cisplatin-induced toxicities. It has been
shown that this is selective in the kidneys, but not other tis-
sues (Verschraagen et al., 2004). More recently, the kinetic
proﬁle of BN7787 and the recommended dosage of the
drugs have been determined (Boven et al., 2005). A dose
of up to 41 mg/m
of the drug was safely tolerated, and a
dose of 18.4 mg/m
was recommended for therapy. The
protective agent enabled safe reduction of the saline dehy-
dration schedule for cisplatin to 1 l.
2.7. Other protective agents
Recent evidence suggests that apoptosis and inﬂamma-
tory mechanisms play an important role in the pathogene-
sis of cisplatin nephrotoxicity (Jo e t al., 2005; Ramesh and
Reeves, 2005). Li et al. (2002) reported that treatment of
rats with the anti-inﬂammatory agent salicylate (100 mg/
kg (bid), i.v. 5 days) reduced cisplatin nephrotoxicity (and
ototoxicity) without adversely aﬀecting its chemotherapeu-
tic eﬀectiveness in suppressing tumour mass and cancer cell
metastasis. A possible mechanism for this action was pro-
vided by Ramesh and Reeves (2004), who indicated that,
in mice, salicylate acted via inhibition of TNFa (an impor-
tant cytokine involved in systemic inﬂammation and the
acute phase response), and that this inhibition may act to
stabilize a cell survival factor. Ramesh and Reeves (2004)
suggested that salicylate co-administration with cisplatin
may even enhance its oncolytic eﬀect. More recently the
same authors suggested that hydroxyl radicals, either
directly or indirectly, activate p38 mitogen-activated
protein kinase, MAPK (which is a cytokine supp ressive
anti-inﬂammatory drug binding protein that regulates
many cellular processes including inﬂammation, cell diﬀer-
entiation, cell growth and death) and that p38 MAPK
plays an important role in mediating cisplatin-induced
acute renal injury and inﬂammation, perhaps through pro-
duction of TNF-a (Ramesh and Reeves, 2005).
It has been shown that the nephrotoxicity of cisplatin in
mice is attenuated when it is given together with oral bis-
muth subnitrate (BSN), which is thought to induce metallo-
thionein, a cysteine-rich protein that protects against heavy
metal toxicity. As BSN is absorbed slowly from the gut, its
eﬃcacy in inducing renal metallothionein is low. Kondo
et al. (2004) attempted to overcome this by dissolving
BSN in citrate buﬀer rather than in normal saline. This
resulted in signiﬁcan tly improving bismuth distribut ion,
renal metallothionein induction and attenuating cisplatin
nephrotoxicity without aﬀecti ng its antitumour activity.
Kohda et al. (2005) reported that administration of
serum thymic factor (FTS) had a beneﬁcial eﬀect against
cisplatin nephrotoxicity in rats in vivo, and also against
cultured porcine epithelial cells in vitro. The exact mecha-
nism by which FTS protects against cisplatin nephrotoxi-
city (or other types of tissue injury) is still unknown,
although several hypotheses have been suggested. It has
been shown that FST doe s not block the uptake of plati-
num into the kidney, nor does it reduce the concentration
of platinum retained by the kidney. The protection was
suggested to involve activation of extracellu lar signal-
regulated protein kinase (ERK). This activation may be
responsible for renal regeneration. Previously, it has been
shown that inhibition of ERK activity enhances sensitivity
to cisplatin cytotoxicity in an ovarian cell line (Wei et al.,
3. Agen ts that augment the nephrotoxicity of platinum
The agents discussed below are summarised in Table 2.
3.1. Inhibitors of renal excretion
Cisplatin accumulates in the cells by carrier-mediated
processes, through probenecid-sensitive organic anion
transporters. Probenecid restricts renal secretion of anionic
drugs through inhibition of the organic anion transport
system(s). Co-administration of probenecid has shown to
B.H. Ali, M.S. Al Moundhri / Food and Chemical Toxicology 44 (2006) 1173–1183 1179
decrease renal excretion of several drugs, including cisplatin
(Taguchi et al., 2005). Probenecid could interfere with tubu-
lar secretion of cisplatin, and thereby could increase its
nephrotoxicity. This is in sharp contrast to the earlier report
of Jacobs et al. (1991), who suggest ed that probenecid may
protect against cisplatin nephrotoxicity in humans, and that
its unique mechanism of action and lack of toxicity make it
ideal to combine with other chemoprotectors.
3.2. Agents that enhance lipid peroxidation
Saad et al. (2001) reported that the administration of
gemcitabine (an anticancer drug that is a new cytarabine
analogue) at a single i.p. dose of (90 mg/kg), followed 4
or 24 h later with cisplatin (6 mg/kg, i.p.) aggrava ted the
biochemical signs of cisplatin-induced nephrotoxicity in
rats through enhanced lipid peroxidation in renal tissues.
In a previous publication, however, Saad et al. (2000) cast
doubt on the importance of lipid peroxidation as a mecha-
nism by which cisplatin induced nephrotoxicity.
3.3. Modulators of nitric oxide (NO)
NO plays an important role in maintaining normal renal
function (Fujihara et al., 2006). Decrease in NO concentra-
tion in the kidneys contributes, at least in part, to cisplatin
nephrotoxicity. The role, however, played by NO or NO
synthase inhibitor in cisplatin nephrotoxicity is not clear.
Srivastava et al. (1996) were among the ﬁrst who provided
evidence for the involvement of NO in cisplatin-nephrotox-
icity. These workers have sh own that the inhibitor of NO
L-arginine methyl ester was eﬀective
in mitigating the lipid peroxidation and the other biochem-
ical changes associated with the administration of cispl atin
nephrotoxicity. This was later conﬁrmed by Saad et al.
(2002) and Saleh and El-Demerdash (2005), who investi-
gated the eﬀect of an NO synthas e inhibitor, 2-amino-
4-methylpyridine, and inhibitor of nitric oxide synthase,
L-NAME, respectively, on cisplatin-induced nephrotoxi-
city in rats, and reported that they both exacerbated the
The broad-spectrum cytoprotective agent amifostine has
been approved by the US Food and Drug Administration
for use in patients receiving cisplatin, with the aim of reduc-
ing its nephrotoxicity. However, as mentioned above, a sin-
gle case report indicated that the combination of the two
drugs in a girl with epithelial cell carcinoma of the ovary
has resulted in the aggravation of cisplatin toxicity (Sastry
and Kellie, 2005). It should be mentioned, however, that
most of the published literature seems to suggest that amifos-
tine is a useful protectant agent against cisplatin toxicities.
4. Conc lusions
Although cisplatin can cause nephro-, neuro-, and other
toxicities, and despite the availability of some newer and
less toxic platinum drugs, cisplatin remains a major anti-
neoplastic drug for the treatment of solid tumours, such
as metastatic bladder, testicular and ovarian carcinomas.
This is because of the proven eﬀectiveness of the drug
and the relatively longer experience with it. Therefore,
strategies of ameliorating the toxicity of cisplatin are of
clinical interest. Several studies have conﬁrmed that ami-
fostine is an eﬀective protectant against cisplatin toxicities.
Many other agents have been shown, in animal models, to
be eﬀective in mitigating these toxicities, most notable of
which are agents interfering with the metabolic pathways
of cisplatin, modulators of nitric acid, and synthetic and
natural antioxidants. The latter are particularly promising
in view of their eﬀectiven ess and relative safety, and are
worth assessing clinically. Agents that can augment cis-
platin nephrotoxicity, for example gemcitabine, an agent
that enhances lipid peroxidation, should not be combined
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A list of some agents reported to augment the nephrotoxicity of cisplatin
Agent Dose, route and duration Species Reference
Nitric oxide synthase inhibitors
3.5 mg/kg/day, i.p., 6 days Rats Saleh and El-Demerdash (2005)
Theophylline 0.8 mg/ml in drinking water, 2 weeks Rats Saad et al. (2004)
Spironolactone 20 mg/kg/day, o.s., 5 days Rabbits Ahmida et al. (2001)
Augmenters of lipid peroxidation
Gemcitabine 90 mg/kg, i.p., once Rats Saad et al. (2001)
Agents causing oxidative stress
Allopurinol 50 mg/kg, s.c., 5 days Rats Erdinc et al. (2000)
NG-nitro-L-arginine methyl ester.
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