Methionine Cancer

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Anti-Cancer Agents in Medicinal Chemistry,2007, 7, 19-34 19

1871-5206/07 $50.00+.00 2007 Bentham Science Publishers Ltd.

The Role of Sulfur in Platinum Anticancer Chemotherapy

Xiaoyong Wang1 and Zijian Guo2,*

1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, 210093, Nanjing

P.R.China and2State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemis-

try and Chemical Engineering, Nanjing University, 210093, Nanjing, P.R. China

Abstract: Sulfur manifests its influence on platinum anticancer chemotherapy in two aspects: endogenous sulfur-

containing molecules such as cysteine, methionine, glutathione, metallothionein and albumin affect the metabolism of

platinum drugs and exert adverse effects on the therapeutic efficacy; exogenous congeners such as amifostine (WR-2721)

and dimesna (BNP7787) mitigate the toxic side effects of platinum drugs and serve as chemoprotectants. The platinum-

sulfur interactions are ubiquitous in the human body and many occurrences encountered during platinum chemotherapy

such as uptake, excretion, resistance, and toxicity are related to them. Thus, sulfur-containing molecules play significant

roles in the anticancer mechanism of platinum drugs. In this review, the platinum-sulfur interactions are summarized in

detail, which may be important for efficient clinical use of the existing platinum agents and beneficial to the rational de-

sign of new generation of platinum-based anticancer drugs.

Key Words: Anticancer drug, Platinum complex, Sulfur, Platinum-sulfur interaction, Chemotherapy, Chemoprotectant, Resis-tance, Sulfur-containing molecules.

INTRODUCTION

Sulfur-containing biomolecules such as cysteine (Cys),methionine (Met), glutathione (GSH), metallothionein (MT)and albumin play significant roles in platinum anticancerchemotherapy because of their high affinity to platinum(II)compounds [1-3]. Sulfur is involved in the entire metabolic

process of platinum drugs, including reactions prior to celluptake, deactivation prior to DNA binding, and formation ofDNA-adduct, etc [4]. The nature of the final products formost of these reactions has been clarified [4-6]. However,the role of sulfur compounds has been controversial. On onehand, the interactions between sulfur-containing moleculesand platinum drugs are considered to have negative effectson the therapeutic efficacy of the drugs [2, 7-9]. For exam-

ple, they have been related to drug detoxification, nephro-toxicity and resistance [10, 11];

strong and irreversible

binding of cisplatin to intracellular thiolate ligands such asGSH and Cys-rich MTs has been considered as a major in-activation step for this drug [12-14];

and reactions of plati-

num drugs with sulfur donors in peptides and proteins arebelieved to alter the conformation of proteins and lead tochanges in biological activity, especially when enzymaticreactions are affected [15]. On the other hand, the platinum-sulfur interactions can be used to produce favorable effectsin the clinical application of Pt-based drugs. It is possiblenow to employ sulfur-containing compounds as chemopro-tectants to mitigate the severe toxic side effects of platinumdrugs and some of them have been registered in a number of

European countries [16-18]. Moreover, the design of newgenerations of platinum-based drugs can be benefited fromthe understanding of these interactions.

*Address correspondence to this author at the State Key Laboratory of Co-ordination Chemistry, Coordination Chemistry Institute, School of Chemis-try and Chemical Engineering, Nanjing University, Nanjing 210093, P.R.China; Fax: +86-25-83314502; E-mail: [email protected]

Most of the sulfur-containing molecules to be discussedin this review are endogenous compounds found in human

body and only those compounds taken in for protective ortherapeutic purposes are alien synthetics. According to theorigins of these molecules, this review is arranged in two

parts: endo-sulfur and exo-sulfur. The first part deals withthe natural sulfur-containing molecules that may potentiallyinfluence the efficacy of the platinum drugs and the second

part concerns the synthetic compounds that may protect thenormal cells from the damage of these drugs. Since manyvaluable reviews on this subject have appeared over theyears [2, 19-21],

this review will concentrate only on the

most recent advances in this area.

ENDO-SULFURA. Endogenous Sulfur-containing Molecules in HumanBody

Sulfur Containing Amino Acids

Sulfur containing amino acids play important roles inmaintaining the integrity of cellular systems by influencingthe cellular redox state and the capacity to detoxify toxiccompounds, free radicals and reactive oxygen species. Me-thionine (Met) and cysteine (Cys) are the two principal sul-fur-containing amino acids in mammals. Both of them con-tribute significantly to the cellular pool of organic sulfur andto the sulfur homeostasis as well as to the regulation of onecarbon metabolism.

Met is an essential amino acid provided by the diet andthe de novo recycling of homocysteine (Hcy) [22]. Apartfrom its role in protein synthesis, Met is the substrate for theformation of S-adenosylmethionine (AdoMet), the widelyutilized methyl donor for DNA, protein and lipid methyla-tions [23]. A broad range of cancer cell lines have been char-acterized by their dependence on Met [24], which is defined

by the inability to grow in a Met-depleted environment sup-


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20 Anti-Cancer Agents in Medicinal Chemistry, 2007, Vol. 7, No. 1 Wang and Guo

plemented with Hcy. In contrast, normal cells are able toefficiently utilize Hcy and sustain growth in the absence ofexternally provided Met [25, 26]. This feature offers the pos-sibility to control selectively the proliferation of Met-dependent cancer cells by depleting Met and the potential todevise a specific and selective therapeutic strategy [27].

Different from Met, the essential amino acid Cys is pro-vided by the diet as a metabolite of Met or obtained from

tissues expressing the enzymes of the trans-sulfuration. Cystakes part in the synthesis of protein and glutathionine (GSH)[28], and reduces the requirements for Met in murine [29]and human [30] cells.

Hcy is a sulfur containing amino acid that plays a signifi-cant role in one carbon metabolism and methylation reac-tions. The only source of Hcy in human body is from thedemethylation of dietary Met. Hcy can be remethylated toform Met again with the aid of Met synthase. In most tissues,the remethylation of Hcy is dependent on the cofactor activ-ity of folate and Vitamin B12. Hcy can also be metabolizedthrough transsulfuration to produce Cys with the aid of Vi-tamin B6-dependent cystathionine -synthase (Fig. (1)) [31,32]. Previous studies have suggested that Hcy is a specific

risk factor and/or a marker for human pathologies such ascardiovascular disease [33-35].

Acomprehensive reviewonsulfur-containingaminoacidsand human disease has appeared recently, which should pro-vide more information for readers who are interested in thissubject [36].

Sulfur Containing Peptide and Proteins

Glutathione (GSH, 1) is a water-soluble tripeptide com-posed of glutamate (Glu), cysteine (Cys) and glycine (Gly).With its intracellular content about 0.510 mM

1[1, 37, 38],

GSH is one of the most abundant non-protein thiols in cells.GSH contains an unusual -peptide bond between glutamateand cysteine, which prevents GSH from being hydrolyzed by

most peptidases. Intracellular GSH is kept in its thiol formby GSH disulfide reductase, a NADPH-dependent enzyme,and hence the mercapto group in GSH is a potent reducingagent. The maintenance of a reduced cellular environment isgreatly dependent on the maintenance of a balanced redox

potential by GSH. As a primary source of cellular nucleo-philes and an important antioxidant, GSH plays a key role inthe detoxification of a variety of electrophilic compoundsand peroxides under catalysis of glutathione S-transferases(GST) and glutathione peroxidases (GPx) [39]. GSH hasvarious physiological functions in cellular defense and

1 Diverse data appeared in literature, varying from 10100 nM to 0.510 mM.

metabolism, including modulation of thiol-disulfide status ofcellular proteins, protection of cells from oxidative stress,synthesis and transport of biologically active endogenoussubstances, detoxification and/or bioactivation of drugs [40-42]. The importance of GSH in human disease has been re-viewed recently [39], thus details in this respect are omittedhere.

Albumin is the most abundant protein in blood plasma,amounting to ca 52% of its proteic composition and pre-senting in concentrations of 40 mg ml-1 (~ 0.6 mM;Mr = 66kDa) in normal individuals [43]. Human serum albumin(HSA) consists of a single chain of 585 amino acids orga-nized in three structurally homologous domains (I, II andIII), each of them contains two sub-domains [44]. The three-

dimensional structure of HSA has been intensively studied[45]. At physiological pH, albumin presents two structuralisomers, N and B. It is basically a helical protein with -helix content of 67%, the helices being bound by 17 disulfide

bridges and leaving only one free thiol (Cys34) in a crevice,which has a strong affinity for metal ions (soft acids). The

physiological functions of HSA include the control of os-motic blood pressure, the transport, metabolism and distri-

bution of endogenous or exogenous substances such as hor-mones, amino acids, fatty acids, metal cations and drugs,deactivation of free radicals in the extracellular medium, andthe source of amino acids for protein synthesis after hydroly-sis [44, 46, 47].

Metallothionein (MT) is a thiol-rich protein found in all

eukaryotes and some prokaryotes and has been studied ex-tensively since its discovery in 1957. MT constitutes a fam-ily of low molecular weight intracellular metalloproteins thathave been subdivided into three classes, i.e. MT-I, MT-II,andMT-III[48]. Mammalian MTs, mostly belonging to MT-I,are composed of a string of 61 or 62 amino acids, 20 ofwhich are conserved Cys residues. These proteins are able to

bind up to seven divalent atoms, mainly metals, and othercompounds, such as free radicals [49]. The metal binding tothe thiol group of Cys residues is very strong, and is dynami-cally controlled by the oxidoreductive environment of the

cells [50-54]. All 20 Cys residues participate in metal bind-ing, and each metal ion (e.g. Zn2+ or Cd2+) is tetrahedrallycoordinated to four Cys thiolate sulfur atoms. MTs are likely

Fig. (1). The metabolism of methionine and homocysteine.

CH3S COOH

H NH2

HS COOH

H NH2

HSCOOH

H NH2VB6

Hcy

Met synthase cystathionine-synthasefolate, VB12

Met Cys

C

O

NH2 CH

COOH CH2

SH

CH2 CH2

O

NH CH C NH CH2COOH

1


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The Role of Sulfur in Platinum Anticancer Chemotherapy Anti-Cancer Agents in Medicinal Chemistry,2007, Vol. 7, No. 1 21

to play important physiological roles in the metabolism andstorage of essential trace metals as well as in the detoxifica-tion of toxic metals such as sequestering Cd

2+, Hg

2+, Au

+,

and Pt2+

ions [55-57], and thereby prevent them from react-ing with other cellular targets. The physiological or pharma-cological functions of MTs could also be extended to thescavenging of radicals, response to stresses, and effective-ness of metallodrugs and alkylating agents [58], however,only that in detoxification of heavy metals is widely accepted

[59].

Human serum transferrin (HTf) is an iron-binding proteinwith a single polypeptide chain of 679 amino acids, includ-ing 9 Met residues and 37 Cys residues (vide infra), and amolecular weight of ca. 80 kDa. The single chain has twosimilar lobes (N- and C-lobe) connected by a short peptide.Each lobe can be further divided into two domains of similarsize, which have alternating -helical and-sheet segments.In human serum, the concentration of transferrin is about 2.5mg/ml (35 M) with 30% occupied with iron [60]. The fun-damental role of transferrin is the binding and transporting ofnon-heme iron into the cell via receptor mediated endocyto-sis [61, 62]. Transferrin may regulate iron metabolism and

protect against the toxic side effects of free iron, but it is also

likely to be involved in the transporting a wide range ofmetal ions other than iron, such as therapeutic metal ions,radioactive diagnostic metal ions, and some toxic metal ions[63]. The functional properties, metal binding properties,structures, and metal delivery potentials of HTf in biomedi-cal processes are skipped here for they have been summa-rized in several reviews recently [61, 64-66].

B. Interactions of Platinum Drugs with Sulfur-containingMolecules

The platinum-sulfur interaction is a complicated issuebecause of the great abundance and vast distribution of sul-fur-containing biomolecules in human body. These interac-tions may occur inside or outside of the cells and are directlyrelated to the metabolism, toxicity and resistance of plati-num-based drugs. It is commonly believed that platinum

drugs exert their antitumoral effect primarily by interactingwith cellular DNA [67, 68]. However, on their way to theDNA target, platinum drugs will inevitably meet a variety ofsulfur-containing molecules. Only those platinum speciesthat have successfully escaped the hijacking of sulfur-containing molecules could finally bind to DNA and lead tothe death of the dividing cells [69-71]. Some of the majorinteractions of platinum drugs with sulfur-containing bio-molecules are summarized in Fig. (2).

With Extracellular Sulfur-containing Molecules

Human serum albumin (HSA) is the most abundantplasma protein and any injected metal drug should havesome kind of interaction with this macromolecule, whichcould crucially determine its bioavailability and toxicology.

Without exception, platinum-based drugs also bind to HSAand such reactions may be related to the metabolism, effi-cacy, and body distribution of the drugs [72, 73].

In fact,

there is about 6598% of cisplatin in blood binds quasi irre-versibly to HSA, which brings cisplatin in circulation. Themajor platinum binding sites in HSA appears to be Metrather than the previously believed Cys34 [74]. In HSA there

Fig. (2). The major platinum-sulfur interactions inside and outside of cell.


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are six Met residues, i.e. Met87, 123, 298, 329, 446, and 548.Among them, Met298 is the most surface accessible residueand thus has been speculated to be the main cisplatin-bindingsite. The other exposed residues are Met87 and Met446.These residues may be involved in the formation of mono-functional adducts orS,N-macrochelates with cisplatin [75].The polypeptide amide, carbonyl and sulfur donor groupscould be additional platinum binding sites in HAS, whichhas been proposed based on FTIR experiments [76].

The kinetic studies of cisplatin with albumin in a simu-lated biological system revealed that cisplatin binding to the

protein obeyed a SN2 mechanism [72]. The apparent pseudo-first-order rate constant kapp correlated linearly with [albu-min]:

kapp = 0.263 + 0.405[albumin]

Antitumor platinum(II) complexes other than cisplatinhave been studied in different animal models for their phar-macokinetics (Fig. (3)). Oxaliplatin exhibited similar [77] orgreater protein binding ability than cisplatin [78] or car-

boplatin [79]. In human plasma, albumin and -globulinsshared similar levels of oxaliplatin within 3 h after i.v. ad-ministration [80]; and equilibrium between oxaliplatin and

albumin alone or total plasma was attained after 24 and 5-6h, respectively, with 7987% of the Pt covalently bound to

purified albumin [81]. However, other recently approvedplatinum-based drugs such as nedaplatin [82] and lobaplatin[83] (Fig. (3)) showed poor association with plasma proteins.

Although the quasi irreversible albumin-cisplatin bindingwas once suggested not to constitute a drug reservoir fortherapeutic purposes, a number of studies showed evidenceof positive clinical effects of this adduct. For example, bothfree and protein-bound cisplatin exhibit similar effects inseven tumor models [84]; administration of cisplatin-HASincreases tumor concentration of Pt [85]; and treatment withthree courses of the adduct leads to a complete remission oflaryngeal carcinoma [86]. The chemotherapeutic effect of

carboplatin could also be enhanced by albumin [87]. On theother hand, the response of hypoalbuminemic patients tocisplatin therapy is poor [88,89]. In addition, decreased

plasma albumin levels increase marrow, nefro-, hepato- oroto-toxicity of cisplatin, as well as the drug levels in preg-nant women and fetus [90-92]. A review chiefly discussesthe interactions of platinum-based metallodrugs with albu-

min has been published recently [93], which should providemore general knowledge on this subject.

The methionine (Met) residue of proteins is one of theprimary target sites for platinum-based drugs. In the case oftransferrin, there are 9 Met residues, i.e. Met26, 109, 256,309, 313, 382, 389, 464, 499, and 37 Cys residues involvedin its structure [94]. Met256 appears to be the preferred

binding site for Pt(II) when it reacts with the whole protein

[95]. The surface-exposed Met499 is an additional bindingsite, but its rate of platination is slower than that of Met256.When Pt(II) reacts with N-lobe alone, the binding occurs atMet313, which is buried in the interlobe contact region ofintact transferrin. Transferrin may take cisplatin into the cellsvia transferrin receptor.

With ca 146 nmol content per milligram of plasma pro-tein, Met itself plays an important role in the metabolism of

platinum anticancer drugs. A variety of biological effects arerelated to the interactions of platinum complexes with Metand its derivatives [96].

Therefore, extensive studies have

been carried out on these interactions in order to understandtheir implications for the platinum chemotherapy.

Methionine coordinates to platinum diamine compounds

in different manners depending on the reactant and reactionconditions (Fig. (4)). The complex [Pt(Met-S,N)2] has beendetected from the urine of patients treated with cisplatin overtwo decades ago [97],

and its geometrical isomers have been

separated and characterized [98]. Recent studies showed thatthe reaction of cisplatin with Met gave rise to the formationof cis-[PtCl(Met)(NH3)2]

+, cis-[PtCl(Met-S,N)(NH3)]

+, cis-

[Pt(Met-S,N)(NH3)2]2+ and bis-monodentate Met adduct cis-

[Pt(Met-S)(MetH-S)(NH3)2]+, apart from the major metabol-

ite [Pt(Met-S,N)2] [99, 100]. The biological role of these ad-ducts is unclear. Early studies found that the mono-Met sub-stituted cisplatin was more nephrotoxic than aquated cis-

platin species, but the specific Met-platinum adduct respon-sible for this nephrotoxicity was not identified [101, 102].

Met was shown to react rapidly with carboplatin to formlong-lived ring-opened complexes, and the stable adduct[Pt(CBDCA-O)(NH3)2(Met-S)] has been characterized [103-105]. Interestingly, a similar ring-opened complex has beendetected in the urine of animals treated with carboplatin.Carboplatin was presumed to be a prodrug of cisplatin, butits aquation rate is too slow to account for its in vivo activity.

Fig. (3). Chemical structures of the platinum drugs used in anticancer chemotherapy.

Pt

H3N

H3N

Cl

Cl

Pt

H3N

H3N

O

O

O

O

Pt

H3N

H3N

O

O

O

Pt

H2N

NH2

O

O

O

O

Pt

N

N

O

O

O

cisplatin

nedaplatin

oxaliplatin

carboplatin lobaplatin

H2

H2


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It is therefore postulated that Met may play a role in the acti-vation of carboplatin [106].

The reactivity of Met with cisplatin, carboplatin and ox-aliplatin has been compared with each other. Carboplatin andoxaliplatin show a different reactivity towards Met from thatof cisplatin. Cisplatin in water is about 4.5-fold more reac-tive with Met than carboplatin [107]. This result is in goodagreement with the early finding that cisplatin was morereactive with sodium thiosulphate than carboplatin [108].The higher stability of the DACH-platinum moiety (DACH= 1,2-diaminocyclohexane) in oxaliplatin leads to a reaction

behavior significantly different from that of cisplatin andcarboplatin. The formation of mixed-ligand adducts as it is inthe case of cisplatin and carboplatin is prevented in ox-aliplatin due to the high stability of Pt(II)-DACH moiety.The discrepancy between the reactions with Met could partlyexplain the therapeutic differences of these drugs, and itcould also provide clues for the presumed unique mode ofaction for oxaliplatin. A noteworthy feature for oxaliplatin isthat Met has a major influence on its binding behavior to 5-guanosine monophosphate (5-GMP) by competing with 5-GMP for the platinum binding sites. The coordination ofoxaliplatin with 5-GMP is inhibited and the Pt-bound 5-GMP can be replaced from [Pt(DACH)(5-GMP)2]

2-by Met,

whereas Met can not be replaced by 5-GMP. The formation

of [Pt(DACH)(Met-S,N)]+ is faster than that of [Pt(DACH)(5-GMP)2]

2- [109, 110]. These observations suggest that thenon-leaving group may affect the formation and stability of

platinum-DNA adducts in the presence of Met [111, 112].

Strong evidence shows that platinum thioether complexesmay be potential intermediates for DNA platination [113-115]. For example, when S-methylglutathione (GSMe) and5-GMP were added to a solution of [Pt(dien)Cl]Cl (dien =diethylenetriamine), coordination of platinum to thioetheroccurred initially, but coordination to the N7 atom of 5-GMP was the eventual thermodynamic outcome [1].

Similar

results were obtained in analogous experiments using Pt(en)Cl2 (en = ethylenediamine), N-AcMet, and 5-GMP as reac-tants, where one of two sulfur-coordinatedN-AcMet ligands

could be replaced by 5-GMP [116]. Other experimentsshowed that the thioether sulfur-bound Met can be displacedfrom [Pt(dien)(Met-S)]

+intra- [117] or inter-molecularly

[118] by guanine at physiological pH. The fact that an in-tramolecular migration of [Pt(dien)]

2+from a kinetically fa-

voured Met to a thermodynamically preferred histidine (His)in different peptides such as His-Met [119], His-Gly-Met andAc-His-Ala-Ala-Ala-Met-NHPh [120] suggests both kineticand thermodynamic stability play important role when cis-

platin binding to biological targets [121].

The reaction between L-Cys and cisplatin has been ex-amined at neutral pH at 37 C [122]. The reaction proceedsthrough a [Pt(NH3)2(Cys)Cl] intermediate that is formed by adirect reaction of cisplatin with Cys. The intermediate un-dergoes parallel reactions with a second Cys to form a

bis(Cys) complex [Pt(NH3)2(Cys)2]and with the starting cis-platin to form a Cys-bridged dinuclear complex. In the pres-ence of excess Cys, the product is predominantly the

bis(Cys) complex (Fig. (5)). The bis(Cys) complex at neutralpH undergoes slow reaction to form a secondary product,presumably [Pt(NH3)(Cys)2], in which one of the Cys acts as

a bidentate chelating agent. When the concentration of Cyswas increased fourfold over cisplatin, the coordinated am-monia in [Pt(NH3)(Cys)2] was removed completely givingrise to the [Pt(Cys)2] as the dominant product where two Cysact as S,N-chelating agents. These intermediates and prod-ucts have been characterized by

195Pt and

15N NMR spec-

troscopy. However, the biological roles of these species arenot reported so far.

With Intracellular Sulfur-containing Molecules

As shown in Fig. (2), cisplatin enters the cell from bloodvia passive diffusion or through metal transporters such asMet-rich copper transporter CTR1 [123]. After hydrolysis incytosol, the active species of cisplatin enters the nuclear en-

velope and binds to DNA, which finally triggers cell-cyclearrest and apoptosis. However, intracellular sulfur-containingmolecules such as GSH [124], MT [125] and thioredoxin[126] would compete for cisplatin with DNA. These reac-tions have been associated with the increased cisplatin resis-tance and inactivation. In fact, the efficacy of platinum-basedanticancer agents is a balance between target efficiency(DNA binding) and metabolism by sulfur nucleophiles [127-130].

The most important non-DNA target of cisplatin is pro-bably GSH, which is present in cells at high concentrations[20]. In cytoplasm, a major fraction (ca 60%) of the intra-cellular cisplatin is conjugated with GSH, and only a smallfraction of cisplatin can bind to DNA [131]. GSH reacts with

cisplatin to form the Pt-GS complex that is active in the inhi-bition of cell-free protein synthesis; in the nucleus, GSH canquench DNA-platinum monoadducts before their conversionto the cross-linking bis-adducts [132]. The existence of Pt-GS complex both in a cell-free system and in murine leuke-mia L1210 cells has been confirmed via direct interaction

between cisplatin and GSH with its molecular mass corre-sponding to chelate bis-(glutathionato)-platinum [131]. OtherPt-GS adducts have also been found via the interaction ofcisplatin analogues and GSH [133-134]. The principal bind-

Fig. (4). Some complexes formed between platinum diamine compounds and methionine.

PtNN

O S

N+N3

O

PtNN

SH2N

O-

O

Pt

NN

S S

O-

O

H3N+ H3N+O-

O


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ing modes in these adducts have been unambiguously identi-fied as either monodentate Pt-GS or bridged Pt-GS-Pt [128,135-138]. Formation of the Pt-GS complex plays a signifi-cant role in the cellular metabolism of cisplatin, because it

reduces the amount of intracellular platinum available forinteraction with DNA and protects dividing cells from cis-

platin toxicity.

The elimination of the Pt-GS complex from tumor cellmay reduce the intracellular accumulation of the platinumcomplex [139]. The inverse correlation between GSH levelsand cisplatin accumulation has been observed in spontane-ously transformed rat ovarian surface epithelial cell lines[140]. The deactivated Pt-GS complex is believed to be ex-

ported by the GS-Xpump [9, 131, 141, 142], which is anATP-dependent export pump localized in the plasma mem-

branes of different organs and cell types. This hypothesis isbased on the transport activity and high affinity of GS-Xpump toward GSH S-conjugates (GS-conjugates), GSH di-

sulfide (GSSG), and cysteinyl leukotrienes [143]. Actually,one of the major functions of the GS-X pump is excretionand/or sequestration of toxic compounds in cellular protec-tion system [139].

GSH can potentially affect cisplatin sensitivity in severalways. In addition to the formation of the deactivated Pt-GScomplex, GSH could directly or indirectly participate inDNA repair. Inhibition of DNA repair in cisplatin-resistanthuman ovarian cancer cells has been achieved by depletion

of GSH with buthionine sulphoximine (BSO), a specific in-hibitor of the GSH-synthetic enzyme -glutamyl Cys syn-thetase (-GCS) [144]; and enhancement of cisplatin cyto-toxicity in several in vitro andin vivo preclinical models may

be the direct result of this depletion [145, 146]. Moreover,the Cys residues in the active site of the high-mobility group(HMG) domain proteins HMG-1 and HMG-2 must be in thereduced state in order to recognize cisplatin-damaged DNA[147]. GSH may play a major role in reducing these residues.Finally, GSH may modulate induction of transcription fac-tors such as c-fos and c-jun that potentially affect DNA re-

pair and apoptosis [148-150].

It was suggested that the reaction of hydrolyzed cisplatinderivatives with sulfur ligands gives a drug reservoir fromwhich the Pt(II)-diammine moiety is slowly released to DNAand thus modulates the kinetics of DNA platination (Fig. (6))[2, 113, 115]. However, this supposition may only fits for the

platinum-thioether adducts since the platinum-thiolate com-

plex is very stable.

A study of competitive binding of Pt(II)complexes with GSH and 5-GMP showed that intermolecu-lar displacement of S-bound deprotonated thiolate by the N7atom of guanine is not possible [151, 152]. In addition, GSHcan easily convert platinum-thioether adducts into thiolateadducts [153, 154], even replace the S, N-chelated L-Metfrom Pt(II) complex to form polynuclear Pt-GS adducts [137,138]. The distinct thermodynamic and kinetic differences

between the platinum-thiolates and platinum-thioethers maybe important in the cellular processing of platinum-protein

Fig. (5). The reaction between cisplatin and cysteine at neutral pH.

Cl-

ClPt

H3N

H3N Cl

Cys

NH3

H3N S

COO-

SPt

H3N

COO-

+H3N

+H3N

H+

SPt

H3N

H2N S

HOOC

NH3+

COO-

S

COO-+H3N

PtH3N

H3N Cl

HS

COO-

NH3+

3Cl-

Cys

NH3

SPt

H2N

H2N S

HOOC

HOOC

SH3N

H3N S

NH3

NH3

-OOC NH3 +

COO-+H3N

Pt Pt

Cl-

SPt

H3N

H3N NH2

COOH

Cys

NH3

SPt

H3N

S NH2

COOH

+H3N COO-

NH3

SPt

H2N

S NH2

HOOC

COOH

k2 = 0.056 M-1S-1

cisplatin

dimer

k3 = 0.24 M- 1S-1

cisplatin

+

k1 = 0.022 M-1S- 1


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adducts [1, 153]. For instance, the substitution of platinum-thioether to -thiolate is an important mechanism in the cir-cumvention of cisplatin induced toxicity by thiol-containing

protective agents (vide infra).

Fig. (6). Intracellular competitive binding and inactivation of cis-

platin derivatives in the presence of sulfur-ligand and DNA (charge

of complexes not shown; X = spectator ligand, Y = nucleophile).

It is believed that an important molecular event in theintracellular inactivation of cisplatin is the displacement ofone or both ammine ligands from the metal. There is strong

evidence that GSH or Met residues in biomolecules can dis-place the ammine from cisplatin derivatives prior to DNAbinding [12, 131, 155]. Recent theoretical studies indicatethat after initial binding of cisplatin hydrolysis products tothioethers or thiols, loss of the ammine trans to this sulfurligand rather than replacement of the sulfur ligand itself byother nucleophiles like guanine-N7 is predicted to be the

predominant reaction [156]. These results would be helpfulfor understanding the real mode of cisplatin inactivation

prior to DNA binding.

C. Correlation between Drug Resistance and Sulfur-containing Molecules

The curative potential of platinum-based drugs is fre-

quently undermined by the acquisition or presence of drugresistance. Multiple potential mechanisms of resistance have

been identified at the cellular and molecular levels [20, 157-159]. One of them is closely related to the inactivation ofdrugs by thiol-containing species such as metallothionein(MT), glutathione (GSH), and thioredoxin (Trx) [160-162],though direct interactions of cisplatin and GSH are negligi-

ble in blood because of the low contentrations of both mole-cules [163]. Intracellular inactivation of the cis-Pt(II) center

by Cys residues of the cytoplasmic GSH or MT beforebinding to DNA is a recognized biochemical mechanism fordrug resistance [164], which is schematized in Fig. (2). Inthis mechanism, the following events contribute to the de-velopment of resistance: decrease in drug accumulation ei-ther due to decreased influx or increased efflux; inactivationof the drug by cytoplasmic or nuclear molecules, such asGSH, MT, or proteins; export of Pt-GS conjugates by GS-X

pump [131]; and binding of GSH to cisplatin-DNA mono-adducts, preventing further crosslinks [165].

Although both GSH and MT can detoxify platinum drugsintracellularly or extracellularly by interacting the SH groupswith the drugs and preventing them from binding to DNA[130, 166], GSH is the critical determinant in the tumor cellresistance to cisplatin and other alkylating agents [167].

There is considerable evidence linking GSH to cisplatin re-sistance [168]. Linear correlations between GSH levels andcisplatin resistance have been reported in human renal [169],

bladder [170] and ovarian [13, 171] cancer cell lines and inhuman ovarian tumour biopsies [172]. The levels of GSH aredetermined by the synthetic enzyme -GCS and the salvageenzyme -glutamyl transpeptidase (-GT, GGT). High levelsof GSH and GSH S-transferases (GSTs, GST), the enzymesthat catalyze the nucleophilic GSH reactivity [173], have

been reported to play a role in the resistance of tumor cells todifferent anticancer drugs, including cisplatin [174-177]. Asdescribed in the last section, GSH reacts with cisplatin andother electrophilic compounds to form deactivated conju-gates that are readily excreted by a GS-conjugated export

pump. This reaction may occur spontaneously or with thehelp of the GSTs [178]. The GS-Pt-SG complexes (Pt : GSH= 1 : 2) have been found in tumor cells [179]. The removalof platinum is accompanied by the depletion of intracellularGSH. The GSH depletion sensitizes cells to many cytotoxicagents including cisplatin through activation of sphingomye-linase (SMase), which increases ceramide levels leading toSMase-induced apoptosis [180]. On the contrary, high intra-cellular concentrations of GSH (up to 10 mM) often correlate

with cisplatin and carboplatin resistance, such as in the caseof the cisplatin-resistant cell line A2780cisR, which pos-sesses elevated levels of GSH [130]. For these reasons, theinteraction of platinum drugs with GSH poses a severe ob-stacle for the design of new platinum-based drugs to over-come the cisplatin resistance [181].

On the other hand, increased levels of MTs have alsobeen found in some cell lines with acquired resistance tocisplatin [20, 179]. Cisplatin binds to MT, with a stoichio-metry of 10 Pt atoms per MT molecule and a binding rateconstant significantly higher than that for GSH [182-184].When cisplatin binds to MT, it loses NH3 ligands and dis-

places heavy-metal cations (e.g., Zn2+

) from MT according tothe reaction

(Zn2+)7-MT + 10(NH3)2Pt2+ (Pt2+)10-MT + 20NH3 + 7Zn2+

Early researches show that some therapeutic drugs (e.g.,cisplatin) induce MT synthesis and cells overexpressing MTare resistant to some of these drugs in vitro [12, 185, 186]. Ithas been postulated that MT could scavenge chemothera-

peutic compounds and nucleophilic radicals, protecting tu-mor cells from death [54, 187]. By protecting malignantcells, MT overexpression has been related to a worse prog-nosis for the patient [188, 189].

However, it is not yet clear

whether MT plays a role in cisplatin resistance since MToverexpression only associates with cisplatin resistance inlimited models [12, 190]. Recent studies report that transfec-tion of the human MT-IIA cDNA into cells conferred over 4-fold resistance to cisplatin [12], and up-to-date studies ap-

pear to show that cisplatin resistance can be prevented orreversed by the modulation of MT synthesis [191]. Thesefindings indicate that the uncertain role of MT is beinggradually refined.

Thioredoxin (Trx) is a redoxactive sulfur-containingprotein induced by various stresses and secreted from cells.It has been reported that cellular levels of Trx, thioredoxinreductase (TrxR), and glutaredoxin (Grx) are associated withcisplatin resistance, where increased cellular activity of the

Pt

H3N

H3N

OH2

X

Pt

H3N

H3N

N7-Gua

X

Pt

H3N

H3N

S-ligand

X

PtH3N

Y

S-ligand

X

DNA binding

GSH/Cys/Metbinding

ammine loss

release from drug reservoir


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Trx system confers resistance to cisplatin [157]. The Trx andGrx systems can be inhibited by Pt-GS complexes, which isconsistent with the correlation between increased Trx andcisplatin resistance [192]. Moreover, acting as a downstreameffector of Smad7, Trx could suppress cisplatin-inducedapoptosis in pancreatic cancer [193]. Reduced Trx is also aninhibitor of ASK1 [194], and the Trx related peroxiredoxinmight protect cancer cells from apoptosis caused by cis-

platin-induced oxidative stress [195].

EXO-SULFUR

A. Toxicity of Platinum Anticancer Drugs

Platinum anticancer drugs usually bring on severe gen-eral toxicity such as nephro- and neurotoxicity during che-motherapy, which may be related to their interactions withMet or Cys residues of proteins and peptides [1]. For exam-

ple, cisplatin depletes protein-bound thiol (SH) groups inrenal cells [196, 197] and inhibits various enzymes such asmitochondrial GSH reductase, Na+-K+-ATPase [198, 199],and respiratory enzymes [200]. Decreased GSH peroxidaseactivity concurrent with GSH depletion has been observed inrat kidneys following exposure to cisplatin [201-203].

Among the common toxicities induced by platinum anti-cancer drugs, nephrotoxicity is the major toxic effect en-countered in the clinical application of cisplatin, which ismainly associated with the damage to the nondividing

proximal tubule cells in the kidney [204]. To avoid or limitthe nephrotoxicity in platinum chemotherapy, it is necessaryto understand how cisplatin is metabolized to a nephrotoxin.In this process, the formation of Pt-GS complex and itstransport out of the cell are the beginning steps [205].

The

exported Pt-GS complex is cleaved to a platinum-cysteinyl-glycine complex by -glutamyl transpeptidase (GGT, a gly-cosylated membrane enzyme) on the cell surface [206, 207],which is further cleaved to a platinum-Cys complex by ami-nodipeptidase N on the cell surface. The platinum-Cys com-

plex is taken into the cell and then converted to a highly re-active thiol by Cys-S-conjugate -lyase [208, 209].

Binding

of the reactive thiol to essential proteins within the cell istoxic [210, 211]. The schematic pathway for the metabolism

of cisplatin to a nephrotoxin is shown in Figs. (2) and (7),respectively.

B. Exogenous Sulfur-containing Molecules as Cytopro-tective Agents

Platinum-based chemotherapy leads to a variety of seri-ous toxicities in clinical practice. However, the introductionof sulfur-containing molecules as cytoprotective agents

could mitigate the severity of the toxic side effects of plati-num drugs [1, 7, 19].

As a chemoprotectant, it should modu-

late the side effects in a beneficial way, but not affect theantitumor activity of the drug, and has no or only mild toxic-ity. Because of the preference of platinum for S-donorligands, the majority of the potential chemoprotectants ex-

plored for platinum-based therapy thus far are sulfur-containing compounds. The protective nature of these com-

pounds is involved in prevention or reversal of Pt-S adductsin proteins. The potential reversibility of Pt-S bonds in the

presence of other sulfur ligands suggests that certain Pt-bound sulfur ligands can be substituted by other sulfur nu-cleophiles, and Pt can be transferred between various S-containing molecules in vivo [117, 212, 213],

which forms

the chemical basis to alleviate the acute platinum toxicityusing chemoprotectants.

Thiocarbonyl and thiol donor compounds are promisingchemoprotectants that have been evaluated in experimentaland/or clinical studies. Among them, sodium thiosulphate(STS) [214], S-[N-(3-aminopropyl)-2-aminoethyl] dihydro-gen thiophosphate (WR2721, amifostine) [215], diethyldi-thiocarbamate (DDTC) [216], disodium 2,2-dithiobisethanesulfonate (BNP7787, dimesna) [217], glutathione (GSH) andits esters [218] have attracted great attention. Other sulfurcontaining compounds such as thiourea, biotin, sulfathiazole,D-penicillamine, methimazole, tiopronin, 4-methylthioben-zoicacid(MTBA), and 2,3-dimercaptosuccinic acid (DMSA)have also been evaluated in preclinical models [219, 220].However, none of them has been proved to be clinically ef-fective as a complete protective agent in human patients.Sulfur-containing amino acids such as L-Cys, L-Met, N-AcCys, and DL-Hcy have been shown to reduce cisplatin-induced toxicity and cisplatin uptake in different cells, there-

Fig. (7). The pathway for the metabolism of cisplatin to a nephrotoxin. The ammine trans to sulfur may be released during this process.

Pt

H3N

H3N

Cl

ClS CH2 CH

C

NH

NH

O

CH2 COOH

C CH2

O

CH COOH

NH2

Pt

H3N

H3N

Cl

S CH2 CH

C

NH2

NH

O

CH2 COOHPtH3N

H3N

Cl

S CH2 CH

COOH

NH2

PtH3N

H3N

Cl

HS CH2 CH

C

NH

NH

O

CH2 COOH

C CH2

O

CH COOH

NH2

Pt

H3N

H3N

Cl

S

GGT Aminodipeptidase

-lyase


9/16


fore have the potential for clinical application as chemopro-tectants [221-223]. Currently, WR2721, GSH, and BNP7787are representatives being applied or investigated in clinic aschemoprotectants, and hence they will be discussed in moredetail in this review.

WR-2721

WR-2721, together with STS and DDTC, belongs to thefirst generation platinum-protective agents and is also the

most extensively evaluated cytoprotective agent. Thiolmoieties in these agents are reactive with the nephrotoxicaquated species of cisplatin [17, 71]. WR-2721 is the onlyclinically approved chemoprotectant for cisplatin therapy[224-226]. Its administration before cisplatin reduces cis-

platin-induced nephrotoxicity, myelosuppression and neuro-toxicity without affecting the antitumor activity of the drug[227-229]. The protective effect of WR-2721 may depend onits tissue-specific accumulation and active cellular metabo-lism mediated by alkaline phosphatases [18]. As schematizedin Fig. (8), WR-2721 is converted in vivo into the more reac-tive thiol form S-2-(3-aminopropylamino) ethanethiol (WR-1065) by the catalysis of alkaline phosphatase [230], whichis found in higher concentrations in normal tissues than in

tumor ones [231-233].Compared with WR-2721, WR-1065 can readily get into

cells, and only the latter can protect cells from cisplatin-induced cytotoxicity in culture experiments [234]. Therefore,WR-2721 is a prodrug and its metabolite WR-1065 is theactive form to protect the general toxicity by interacting withcisplatin in normal tissues. WR-1065 reacts with cisplatinsimilarly to GSH and forms Pt-thiolate adducts [71]. PlasmaWR-2721 declines rapidly due to the dephosphorylation andthe resulting WR-1065 has a short initial half-life due to itsfast uptake by tissues and oxidation to disulfides, that even-tually constitutes the major fraction in blood plasma and mayserve as a pool for WR-1065 [16]. WR-1065 is capable ofreversing monofunctional Pt-Met bonds, but this reversal is

slow compared to that achieved with STS or DDTC. Thislow capacity has been taken as an explanation for the lack ofnephroprotection when WR-2721 is given after platinumtherapy [235]. WR-1065 is often administered to alleviatetoxicities of platinum-based drugs and other alkylatingagents such as cyclophosphamide [236, 237]. However, thereactivity of WR-2721 is not negligible and the alkaline

phosphatase activity is not necessarily required if the con-centrations of WR-2721 are sufficiently high. Kinetic dataindicate that WR-2721 reacts with cisplatin and carboplatinwith rate constants amounting to approximately 50% ofthose determined for WR-1065 [238]; and in vitro studiesshow that HPLC profiles of reaction products after incuba-tion of WR-2721 and WR-1065 with [Pt(DACH)(malonato)]are indistinguishable. Although WR-2721 is relatively stable

in aqueous solution, its reaction with cisplatin (1:1) is com-paratively fast (dephosphorylation time, 1.5 h) [239].

The ability of WR-2721 to reduce DNA platination isschedule-dependent in vitro, with pre-exposure or simultane-ous exposure being more effective than post-exposure toWR-2721 [240]. However, protection from platinum-DNAadducts is unlikely to occur in blood cells at clinicallyachievable plasma concentrations of both cisplatin and WR-

2721, which has been manifested by the results of in vitroexperiments in peripheral blood mononuclear cells [241] andfindings in leukocytes from patients treated with cisplatinwith or without prior administration of WR-2721 [242]. ThePt-DNA adduct level in cancer patients can be influenced byWR-2721, which further demonstrated its modulating abilityon cisplatin toxicity [227]. Both myeloprotective and neuro-

protective properties of WR-2721 have been substantiated orsuggested by in vitro studies in hematopoietic progenitorcells [243, 244] or by neurite outgrowth assay [245] in the

presence of carboplatin, respectively.

WR-2721 accumulates more rapidly and effectively inliver, lung, kidney, bone marrow, intestinal mucosa and skinthan in tumors after administration to tumor-bearing mice

and rats [246]. Various preclinical models have demon-strated the partial protection from cisplatin-induced nepro-toxicity [247, 248] and carboplatin-induced myelotoxicity[249, 250].

Partial protection from both cisplatin-induced

neurotoxicity [251], nephrotoxicity [252], ototoxicity [253]and carboplatin-induced myelosuppression

[254, 255] has

been confirmed or revealed by small comparative trials withor without WR-2721; and partial protection from nephro-toxicity induced by a high-dose chemotherapy regimen com-

prising carboplatin plus ifosfamide plus etoposide has alsobeen reported. [256] The effects of WR-2721 depend on thetiming of administration. In mice, to reduce the renal injuryand lethality, WR-2721 must be given shortly before cis-

platin, indicating WR-2721 prevents rather than reverse cel-lular damage [247]. The phase I clinical studies show thatWR-2721 premedication permits a slight increase in bothcisplatin [257] and carboplatin doses [258] as compared totheir standard amounts. Higher therapeutic benefit has beendemonstrated in melanoma patients treated with elevatedcisplatin doses under WR-2721 protection, which produceonly transient nephrotoxicity in a limited number of patients[259].

WR-2721 has only a minor influence on the pharmacoki-netics of cisplatin [260], however, in the case of carboplatin,higher platinum concentrations in plasma and tissues andenchanced antitumour activity in mice were observed [250,261]. Therefore, the pharmacokinetic influence of WR-2721is dependent on the nature of the drugs themselves.

Fig. (8). Dephosphorylation of WR-2721 catalysed by alkaline phosphatase.

SHHN(H2C)3 (H2C)2H2NP O

OH

OH

HN(H2C)3 S(H2C)2H2N

WR-1065

alkaline phosphatase

WR-2721


10/16


WR-2721 may be considered as a chemoprotectant forthe reduction of nephrotoxicity, but there are some reserva-tions regarding its routine use for the prevention of neuro-toxicity or otoxicity due to insufficiency of available data.Furthermore, WR-2721 may cause an increase in nausea andvomiting as well as transient hypotension in some patients.Only after these problems get resolved can a broader use ofWR-2721 in clinic becomes possible.

GSHGlutathione (GSH) is a ubiquitous intracellular sulfur-

containing tripeptide that displays a variety of cellular func-tions (vide supra). As a detoxifying agent, GSH protectsDNA by scavenging intracellular cisplatin [262] and com-

promises the efficacy of the drug; as a cytoprotective agent,however, GSH alleviates drug induced toxicity and possessesa great advantage of lacking major toxicity. For this reason,exogenous GSH could be introduced into the body to realizethe protective intention. The protective effect of GSH seemsto depend on its tissue-specific accumulation and its activecellular metabolism, mediated by -GT [263]. ExtracellularGSH degrades with the aid of-GT; the degradation productcysteinylglycine shows higher reactivity than GSH towards

cisplatin and inactivates the drug more rapidly, which mayplay a key role in the protective mechanism [264].

Currently, GSH is the most extensively explored experi-mental cytoprotectant against cisplatin toxicity [265, 266]. Itis well documented that the renal toxicity [267] and the neu-rotoxic effects [96, 268-270] induced by cisplatin can bealleviated or even prevented by GSH. The cisplatin dosecould be escalated to 175% of the standard amount when thedrug was administered with GSH in a phase I trial [271].Several studies in animals demonstrate that GSH adminis-tered prior to or after cisplatin can decrease the acute lethaltoxicity, and the protective concentrations of GSH appear notto affect the antitumor effects of cisplatin [272-274].

In addi-

tion, GSH can also provide chemoprotection from carbo-

platin ototoxicity [275] and oxaliplatin neurotoxicity [276].Moreover, the esters of GSH can also ameliorate cisplatin-induced nephro- and neurotoxicity in different animal mod-els [205].

BNP7787

BNP7787 (2) is the only second generation cytopro-tectant coming to an advanced clinical stage, and is currentlyunder clinical investigation to protect or mitigate toxicitiesassociated with platinum-based chemotherapy, such as neph-rotoxicity and neurotoxicity [17, 217]. Another cytoprotec-tant closely related to BNP7787 is 2-mercaptoethane sul-fonate (mesna, 3), a commonly used nephroprotectant inifosfamide therapy [277]. The efficacy of mesna in prevent-ing cisplatin-induced nephrotoxicity is still under preclinical

evaluations [278] though it could not be proved in early pre-clinical studies [279, 280].BNP7787 is the dimer of mesna,

but their biochemical and biomedical properties are differentfrom each other.

Mesna distributes mainly in the extracellular compart-ment, which differs markedly from WR1065 that distributesequally between the extra- and intracellular compartments[262, 236].The reaction of mesna with cisplatin is similar tothe cytoprotective mechanism of GSH, also involving theformation of Pt-thiolate adducts [281]. In contrast to mesna,

BNP7787 is inert and relatively stable in blood plasma. Itdoes not interfere with the in vitro andin vivo antitumor ac-tivity of cisplatin and carboplatin [277]. This may be due tothe slow reactivity and short in vivo residence time ofBNP7787 (ca 2 h), together with the much lower concentra-tion of mesna in the circulation. The nephro- and neuropro-tective effects produced by BNP7787 given to rats shortly

before cisplatin and carboplatin enable the maximal in-creases in tolerable doses of both drugs [17]. BNP7787 iscleared rapidly from the blood via the kidneys, where it isreduced to the pharmacologically active thiol form mesnawithin the tubular epithelium by a mechanism involving cy-tosolic GSH reductase [282, 283]. BNP7787 reacts morerapidly with the monoaquated species of cisplatin than theunhydrolyzed drugs, and the nephroprotective properties are

attributed to specific neutralization of the aquated species ofcisplatin in the renal tubules [284]. Phase I clinical and

pharmacokinetic studies show that BNP7787 produces littletoxicity and does not influence the pharmacokinetics of cis-

platin [285]. BNP7787 is currently in phase III trials in theUSA and Europe for the prevention of cisplatin-induced neu-rotoxicity [217].

Others

Diethyldithiocarbamic acid (DDTC, 4) has been shownto reduce cisplatin-induced nephrotoxicity in several animalstudies and in patients when administered after the drug[286]. DDTC could remove platinum-bound biological nu-cleophiles, resulting in the formation of Pt(DDTC)2, and

restore, at least in part, several enzyme activities inhibited bycisplatin. This restoration may be resulted from platinumremoval from Met or Cys residues [287]. However, the useof DDTC in the clinic has been impeded by severe sympa-thetic dysautonomia (flushing, diaphoresis and tachycardia)[281]. The sodium salt of DDTC, sodium diethyldithiocar-

bamate (NaDDTC), and its dimer, bis(N,N-diethylthiocarba-moyl)disulfide (disulfiram), have been extensively studied ascytoprotectants; but randomized trials did not give positivesupport to the promising results from preclinical and earlyclinical studies [288, 289].

-Lipoic acid (thioctic acid, 5) is an essential cofactor formitochondrial enzymes that has been probed as a biologicalantioxidant and a potent free-radical scavenger [290]. Theability of -lipoic acid to bind metal and regenerate GSH

S

O

O-Na+

O

O

O-Na+

CH2CH2 S S CH2CH2 S O OH2 CH2C-S S

O

O-

Na+

2 3

C2H5

C2H5

HS

N

S

4

S S

(CH2)4 C

O

OH

5


11/16


makes it possible as a chemoprotectant for platinum therapyand the suitability is currently under clinical evaluation[291]. Beneficial effects were observed in a few patients whohad developed a neuropathy following combination therapywith oxaliplatin plus raltitrexed [292]. Otoprotective [291,293] and nephroprotective effects in rats [294], both associ-ated with a restoration of antioxidant enzyme activities, have

been reported.

Sodium thiosulfate (STS, Na2S2O3) can be cleared rap-idly from the circulation via kidneys [295], therefore it hasbeen explored for protective properties to reduce the neph-rotoxicity of cisplatin [296]. In addition, STS has beenshown to protect against carboplatin ototoxicity in both ani-mal and human studies [275]. However, inactivation of cis-

platin by STS was observed in preclinical studies when bothagents were administered to the same compartment [297,298]. Although the inactivation could be offset by a moretolerable cisplatin dose resulting from nephroprotective ef-fects, cumulative neurotoxicity prohibits application of sucha high-dose regimen [299]. For this reason, STS has mainly

been studied as an intravenous cytoprotectant to neutralizesystemic platinum cooperatively with intracavitary high-dosecisplatin [300];

but this treatment modality has remained

experimental, since intracavitary administration of cisplatinhas not become a routine practice.

D-Methionine (D-Met) is one of the most effective sul-fur-containing compounds for protecting against cisplatinnephrotoxicity without interfering with its antitumor activity[301]. D-Met behaves differently from other chemoprotec-tants in that it is ineffective against melphalan toxicity butvery effective against cisplatin [302]. D-Met can protect haircells from cisplatin damage in rats or inner hair cells fromcarboplatin damage in chinchillas [303]. As one of the mosteasily oxidizable amino acids, D-Met may act as a free radi-cal scavenger to protect cochlear tissue and hence provideschemoprotection from carboplatin ototoxicity [275].

Finally, the antithyroid drug methimazole has a free SHgroup that could potentially protect against cisplatin-inducedacute nephrotoxicity in vivo [304].

CONCLUDING REMARKS

This review presents an overview about the impact ofsulfur on the platinum anticancer chemotherapy. Based onthe experimental facts found over the years, it can be con-cluded that sulfur is a double-edged sword in the platinumchemotherapy: it compromises the efficacy of platinum-

based drugs on one side,it provides protection against toxic-ity induced by platinum-based drugs on the other side. The

platinum-sulfur interactions exist in almost every process ofplatinum chemotherapy, but there are still a number of ambi-

guities concerning the mechanism of action and the implica-tion of the interactions. Therefore, continuing research in thisarea is highly expected in the coming years. New findings onthese aspects would be helpful for effective use of the exist-ing platinum drugs and be beneficial to the design of new

platinum-based drugs. For example, recent studies have re-vealed that the transport, uptake, subcellular distribution andexport of a substantial fraction of platinum drugs are influ-enced by transporters and metallochaperones that normallymanage Cu homeostasis, especially the Met-rich uptake

transporter CTR1 [123, 305]. However, it is not clearwhether platinum drugs are actually transported into/out ofcells by the Cu transporters or the effect is merely a secon-dary one. In addition, whether any of the platinum drugs isactually the substrate for these transporters and whether sul-fur plays a role in this process are still open questions. Re-searches on such fields are full of challenges, but the greatvalue behind them deserves the endeavor.

ACKNOWLEDGEMENT

We are grateful for the financial supports from the Na-tional Science Foundation of China (No.s 20231010,20228102 and 30370351), China Postdoctoral ScienceFoundation (No. 2003034374) and the Natural ScienceFoundation of Jiangsu Province (No. BK 2005209).

ABBREVIATIONS

ASK1 = Apoptosis signal-regulating kinase 1

BNP7787 = Disodium 2,2-dithiobisethane sulfonate;dimesna

BSO = Buthionine sulphoximine

CBDCA = Cyclobutanedicarboxylate

Cys = Cysteine

DACH = 1,2-Diaminocyclohexane

DTTC = Diethyldithiocarbamate

ESMS = Electrospray mass spectrometry

-GCS = -Glutamyl cysteine synthetase

GGT, -GT = -Glutamyl transpeptidase

Grx = Glutaredoxin

GSH = L--Glutamyl-L-cysteinyl-glycine; (reduced)glutathione

GSSG = Glutathione disulfide

GST, GST = Glutathione S-transferase ()

5-GMP = 5-Guanosine monophosphate

HAS = Human serum albumin

Hcy = Homocysteine

His = Histidine

HMG = High-mobility group

Mesna = 2-Mercaptoethanesulfonate

Met = Methionine

MT = Metallothionein

N-AcCys = N-acetylcysteine

STS = Sodium thiosulofate

Trx = Thioredoxin

TrxR = Thioredoxin reductase

WR-2721 = S-[N-(3-amiopropyl)-2-aminoethyl]dihydrogen thiophosphate; amifostine

WR-1065 = S-2-(3-aminopropylamino)ethanethiol


12/16


REFERENCES

[1] Reedijk, J.; Teuben, J. M. In Cisplatin: Chemistry and Biochemis-try of a Leading Anticancer Drug, Lippert, B. Ed.; Wiley-VCH:Weinheim, Germany, 1999; pp. 339-362.

[2] Reedijk, J. Chem. Rev. 1999,99, 2499.

[3] Guo, Z. J.; Sadler, P. J. Adv. Inorg. Chem. 2000, 49, 183.

[4] Zhao, Z.; Tepperman, K.; Dorsey, J. G.; Elder, R. C. J. Chroma-togr. Biomed. Appl. 1993, 615, 83.

[5] Norman, R. E.; Ranford, J. D.; Sadler, P. J.Inorg. Chem. 1992, 31,877.

[6] Bernareggi, A.; Torti, L.; Facino, R. M.; Carini, M.; Depta, G.;Casetta, B.; Farrell, N.; Spadacini, S.; Ceserani, R.; Tognella, S. J.Chromatogr.B. 1995, 609, 247.

[7] Dorr, R. T. In Platinum and other metal coordination compoundsin cancer chemotherapy, Pinedo, H. M.; Schornagel, J. H. Eds.;Plenum Press: New York, 1996, pp. 131-154.

[8] Wang, D.; Lippard, S.J.Nat. Rev. Drug Discov.2005, 4, 307.

[9] Jamieson, E. R.; Lippard, S. J. Chem. Rev.1999,99, 2467.

[10] Giaccone, G.Drugs2000, 59, 9.

[11] Kartalou, M.; Essigmann, J. M.Mutat. Res.2001, 478, 23.

[12] Kelley, S. L.; Basu, A.; Teicher, B. A.; Hacker, M. P.; Hamer, D.H.; Lazo, J. S. Science1988, 241, 1813.

[13] Godwin, A. K.; Meister, A.; Odwyer, P. J.; Huang, C. S.; Hamilton,T. C.; Anderson, M. E. Proc. Natl. Acad. Sci. USA1992, 89, 3070.

[14] Kozelka, J.; Legendre, F.; Reeder. F.; Chottard, J.-C. Coord. Chem.Rev.1999, 190-192, 61.

[15] Wang, K.; Lu, J.; Li, R. Coord. Chem. Rev.1996, 151, 53.[16] Korst, A. E. C.; Eeltink, C. M.; Vermorken, J. B.; van der Vijgh,

W. J. F.Eur. J. Cancer1997,33, 1425.

[17] Hausheer, F. H.; Kanter, P.; Cao, S.; Haridas, K.; Seetharamulu, P.;Reddy, D.; Petluru, P.; Zhao, M.; Murali, D.; Saxe, J. D.; Yao, S.;Martinez, N.; Zukowski, A.; Rustum, Y. M. Semin. Oncol. 1998,25, 584.

[18] Jakupec, M. A.; Galanski, M.; Keppler, B. K. In Metal ions inbiological systems, Sigel, A.; Sigel, H. Eds.; Marcel Dekker, Inc.:New York, 2004; Vol. 42, pp. 179-208.

[19] Cvitkovic, E. Cancer Treat. Rev. 1998, 24, 265.

[20] Perez, R. P.Eur. J. Cancer1998, 34, 1535.

[21] Hanigan, M. H.; Devarajan, P. Cancer Therapy 2003, 1, 47.

[22] Finkelstein, J. D. Semin. Thromb. Hemost.2000,26, 219.

[23] Ravanel, S.; Block, M. A.; Rippert, P.; Jabrin, S.; Curien, G.; R-beill, F.; Douce, R.J. Biol. Chem. 2004, 279, 22548.

[24] Hoffman, R. M.In Vitro1982, 18, 421.

[25] Guo, H. Y.; Herrera, H.; Groce, A.; Hoffman, R. M. Cancer Res.1993, 53, 2479.

[26] Kenyon, S. H.; Waterfield, C. J.; Timbrell, J. A.; Nicolaou, A.Biochem. Pharmacol.2002, 63, 381.

[27] Pavillard, V.; Drbal, A. A. A.; Swaine, D. J.; Phillips, R. M.; Dou-ble, J. A.; Nicolaou, A.Biochem. Pharmacol.2004,67, 1587.

[28] Lu, S. C. FASEB J.1999, 13, 1169.

[29] Djurhuus, R.; Svardal, A. M.; Mansoor, M. A.; Ueland, P. M. Car-cinogenesis1991, 12, 241.

[30] Di Buono, M.; Wykes, L. J.; Ball, R. O.; Pencharz, P. B. Am. J.Clin. Nutr.2001,74, 761.

[31] Houze, P.; Gamra, S.; Madelaine, I.; Bousquet, B.; Gourmel, B.J.Clin. Lab. Anal.2001, 15, 144.

[32] Chassaing, C.; Gonin, J.; Wilcox, V. S.; Wainer, I. W.J. Chroma-togr. B.1999, 735, 219.

[33] Clarke, R.; Daly, L.; Robinson, K.; Naughten, E.; Cahalane, S.;

Fowler, B.; Graham, I.N. Engl. J. Med.

1991

,324

, 1149.[34] Kang, S. S.; Wong, P. W. K.; Malinow, M. R. Ann. Rev. Nutr.1992, 12, 279.

[35] Nekrassova, O.; Lawrence, N. S.; Compton, R. G. Talanta 2003,60, 1085.

[36] Townsend, D. M.; Tew, K. D.; Tapiero, H.Biomed. Pharmacother.2004, 58, 47.

[37] Goto, S.; Yoshida, K.; Morikawa, T.; Urata, Y.; Suzuki, K.; Kondo,T. Cancer Res.1995, 55, 4297.

[38] Timmer-Bosscha, H.; Mulder, N. H.; de Vries, E. G. E.Br. J. Can-cer1992, 66, 227.

[39] Townsend, D. M.; Tew, K. D.; Tapiero, H.Biomed. Pharmacother.2003, 57, 145.

[40] Dolphin, D.; Poulson, R.; Avramovic, O. Eds. Glutathione: Chemi-cal, Biochemical, and Medical Aspects, John Wiley & Sons, NewYork, 1989.

[41] Hogarth, L.; English, M.; Price, L.; Wyllie, R.; Pearson, A. D. J.;Hall, A. G. Cancer Chemother. Pharmacol.1996, 37, 479.

[42] Paolicchi, A.; Lorenzini, E.; Perego, P.; Supino, R.; Zunino, F.;Comporti, M.; Pompella, A.Int. J. Cancer2002, 97, 740.

[43] Kratz, F. In Metal Complexes in Cancer Chemotherapy, Keppler,

B. K. Ed.; VCH: 1993, p. 391.[44] Carter, D. C.; Ho, J. X.Adv. Protein Chem. 1994, 45, 153.

[45] Sugio, S.; Kashima, A.; Mochizuki, S.; Noda, M.; Kobayashi, K.Protein Eng. 1999, 12, 439.

[46] He, X. M.; Carter, D. C.Nature1992, 358, 209.

[47] Kragh-Hansen, U.Dan. Med. Bull.1990, 37, 57.

[48] Hamer, D. H.Annu. Rev. Biochem. 1986, 55, 913.

[49] Kgi, J. H. R.; Schffer, A.Biochemistry1988, 27, 8509.

[50] Fischer, E. H.; Davie, E. W. Proc. Natl. Acad. Sci. USA1998, 95,3333.

[51] Jacob, C.; Maret, W.; Valle, B. L. Proc. Natl. Acad. Sci. USA 1998,95, 3488.

[52] Jiang, L. J.; Maret, W.; Valle, B. L. Proc. Natl. Acad. Sci. USA1998, 95, 3483.

[53] Jiang, L. J.; Maret, W.; Valle, B. L. Proc. Natl. Acad. Sci. USA

1998, 95, 9146.

[54] Lazo,J.S.; Kuo, S. M.; Woo, E. S.; Pitt, B. R. Chem. Biol. Interact.

1998, 111112, 255.[55] Lemkuil, D. C.; Nettesheim, D.; Shaw, C. F. III; Petering, D. H.J.

Biol. Chem. 1994, 269, 24792.

[56] Morcillo, M. A.; Santamaria, J.Biometals 1996, 9, 213.

[57] Saito, S.; Kurasaki, M. Res. Commun. Mol. Pathol. Pharmacol.

1996, 93, 101.

[58] Kang, Y. J. Proc. Soc. Exp. Biol. Med.1999, 222, 263.

[59] Klaassen, C. D.; Liu, J.; Choudhuri, S. Annu. Rev. Pharmacol.Toxicol.1999, 39, 267.

[60] Leibman, A.; Aisen, P.Blood1979,53, 1058.

[61] Li, H.; Qian Z. M.Med. Res. Rev. 2002, 22, 225.

[62] Qian, Z. M.; Li, H.; Sun, H.; Ho, K. Pharmacol. Rev. 2002, 54,561.

[63] Sun, H.; Li, H.; Sadler, P. J. Chem. Rev.1999, 99, 2817.

[64] Chasteen, N. D.; Woodworth, R. C. InIron Transport and Storage,Ponka, P.; Schulman, H. M.; Woodworth, R. C. Eds.; CRC Press:

Florida, Boca Raton, 1990; pp. 69-83.[65] Baker, E. N.Adv. Inorg. Chem.1994, 41, 389.

[66] Aisen, P.Metal Ions Biol. Syst.1998, 35, 585.

[67] Gelasco, A.; Lippard, S. J. Top. Biol. Inorg. Chem.1999, 1, 1.

[68] ODwyer, P. J.; Stevenson, J. P.; Johnson, S. W. In Cisplatin:Chemistry and Biochemistry of a Leading Anticancer Drug, Lip-pert, B. Ed.; Wiley-VCH: Zrich. 1999, pp. 29-70.

[69] Demarcq, C.; Bunch, R. T.; Creswell, D.; Eastman, A. Cell GrowthDiffer.1994, 5, 983.

[70] Chu, G.J. Biol. Chem.1994, 269, 787.

[71] Dabrowiak, J. C.; Goodisman, J.; Souid, A.-K. Drug Metab. Dis-pos.2002, 30, 1378.

[72] Nagai, N.; Okuda, R.; Kinochita, M.; Ogata, H.J. Pharm. Pharma-col. 1996, 48, 918.

[73] Timerbaev, A. R.; Aleksenko, S. S.; Polec-Pawlak, K.; Ruzik, R.;Semenova, O.; Hartinger, C. G.; Oszwaldowski, S.; Galanski, M.;Jarosz, M.; Keppler, B. K.Electrophoresis2004, 25, 1988.

[74] Pizzo, S. V.; Swaim, M. W.; Roche, P. A.; Gonias, S. L. J. Inorg.Biochem. 1988, 33, 67.

[75] Ivanov, A. I.; Christodoulou, J.; Parkinson, J. A.; Barnham, K. J.;Tucker, A.; Woodrow, J.; Sadler P. J. J. Biol. Chem. 1998, 273,14721.

[76] Neault, J. F.; Tajmir-Riahi, H. A. Biochim. Biophys. Acta 1998,1384, 153.

[77] Pendyala, L.; Creaven, P. J. Cancer Res.1993, 53, 5970.

[78] Kizu, R.; Higashi, S.; Kidani, Y.; Miyazaki, M. Cancer Chemother.Pharmacol. 1996, 31, 475.


13/16


[79] Boughattas, N. A.; Hecquert, B.; Fournier, C.; Bruguerolle, B.;Trabelsi, H.; Bouzouita, K.; Omrane, B.; Levi, F. Biopharm. DrugDispos.1994, 15, 761.

[80] Allain, P.; Heudi, O.; Cailleux, A.; Le Bouil, A.; Larra, F.; Bois-dron-Celle, M.; Gamelin, E.Drug Metab. Dispos.2000,28, 1379.

[81] Graham, M. A.; Lockwood, G. F.; Greenslade, D.; Brienza, S.;Bayssas, M.; Gamelin, E. Clin. Cancer Res. 2000,6, 1205.

[82] Ota, K.; Oguma, T.; Shimamura, K. Anticancer Res. 1994, 14,1383.

[83] Mross, K.; Meyberg, F.; Fiebig, H.H.; Hamm, K.; Hieber, U.;

Aulenbacher, P.; Hossfeld, D.K. Onkologie, 1992, 15, 139.[84] deSimone, P. A.; Brennan, L.; Cattaneo, M. L.; Zukka, E. Proc.Am. Soc. Clin. Oncol. 1987, 6, 33.

[85] Holding, J. D.; Lindup, W. E.; van Laer, C.; Vreeburg, G. C. M.;Schiling, V.; Wilson, J. A.; Stell, P. M. Br. J. Clin. Pharmacol.1992, 33, 75.

[86] Vreeburg, G. C. M.; Stell, P. M.; Holding, J. D.; Lindup, W. E. J.Laryngol. Otol. 1992, 106, 832.

[87] Ni, J.; Wang, Y.; Wang, Q.; Lu, L.; Zheng, Q. Zhongguo YiyuanYaoxue Zazhi 1996, 16, 246.

[88] Holding, J. D.; Lindup, W. E.; Bowdler, D. A.; Siodlak, M. Z.;Stell, P. M.Br. J. Clin. Pharmacol.1991, 32, 173.

[89] Espinosa, E.; Feliu, J.; Baron, M. G.; Sanchez, J. J.; Ordonez, A.;Espinosa, J.Lung Cancer1995, 12, 67.

[90] Belinson, J. L.; Jarrell, M. A.; McClure, M.; Kulig, P. M.; Badger,G. J. Gynecol.Oncol. 1990, 37, 93.

[91] Zemlickis, D.; Klein, J.; Moselhy, G.; Koren, G. Med. Pediatr.

Oncol. 1994, 23, 476.[92] Stewart, D. J.; Dulberg, C. S.; Mikhael, N. Z.; Redmond, M. D.;

Montpetit, V. A.; Goel, R. Cancer Chemother. Pharmacol. 1997,40, 293.

[93] Esposito, B. P.; Najjar, R. Coord. Chem. Rev. 2002, 232, 137.

[94] MacGillivray, R. T. A.; Mendez, E.; Sinha, S. K.; Sutton, M. R.;Lineback-Zins, J.; Brew, K. Proc. Natl. Acad. Sci. USA 1982, 79,2504.

[95] Cox, M. C.; Barnham, K. J.; Frenkiel, T. A.; Hoeschele, J. D.;Mason, A. B.; He, Q.-Y.; Woodworth, R. C.; Sadler, P. J. J. Biol.Inorg. Chem.1999, 4, 621.

[96] Reedijk, J. Proc. Natl. Acad. Sci. USA2003, 100, 3611.

[97] Riley, C. M.; Sternson, L. A.; Repta, A. J.; Slyter, S. A.Anal. Bio-chem. 1983, 130,203.

[98] Murdoch, P. del S.; Ranford, J. D.; Sadler, P. J.; Berners-Price, S. J.Inorg. Chem. 1993, 32,2249.

[99] Liu, Q.; Zhang, J. Y.; Ke, X. K.; Mei, Y. H.; Zhu, L. G.; Guo, Z. J.

J. Chem. Soc., Dalton Trans.2001, 911.[100] Heudi, O.; Cailleux, A.; Allain, P.J.Inorg.Biochem. 1998,71, 61.

[101] Daley-Yates, P. T.; McBrien, D. C. H. Chem. Biol. Interact. 1982,40, 325.

[102] Alden, W. W.; Repta, A. J. Chem. Biol. Interact. 1984, 48, 121.

[103] Barnham, K. J.; Frey, U.; Murdoch, P. del S.; Ranford, J. D.;Sadler, P. J.J. Am. Chem. Soc. 1994, 116, 11175.

[104] Barnham, K. J.; Djuran, M. I.; Murdoch, P. del S.; Ranford, J. D.;Sadler, P. J.Inorg. Chem. 1996,35, 1065.

[105] Liu, Q.; Lin, J.; Jiang, P. J.; Zhang, J. Y.; Zhu, L. G.; Guo, Z. J.Eur. J. Inorg. Chem. 2002, 2170.

[106] Guo, Z. J.; Hambley, T. W.; Murdoch, P. del S.; Sadler, P. J.; Frey,U.J. Chem. Soc.,Dalton Trans. 1997, 469.

[107] Heudi, O.; Mercier-Jobard, S.; Cailleux, A.; Allain, P. Drug Dis-pos. 1999, 20, 107.

[108] Efferink, F. E.; van der Vigh, W. J. F.; Klein, I.; Pinedo, H. M.Clin. Chem. 1986, 32, 641.

[109] Kng, A.; Strickmann, D. B.; Galanski, M.; Keppler, B. K. J.Inorg. Biochem.2001, 86, 691.

[110] Strickmann, D. B.; Kng, A.; Keppler, B. K.Electrophoresis 2002,23, 74.

[111] Vrana, O.; Brabec, V.Biochemistry 2002, 41, 10994.

[112] Williams, K. M.; Rowan, C.; Mitchell, J. Inorg. Chem. 2004, 43,1190.

[113] van Boom, S. S. G. E.; Reedijk, J. J. Chem. Soc. Chem. Commun.1993, 1397.

[114] Barnham, K. J.; Djuran, M. I.; Murdoch, P. del S.; Sadler, P. J.J.Chem. Soc. Chem. Commun.1993, 721.

[115] Teuben, J. M.; Reedjik, J.J. Biol. Inorg. Chem. 2000, 5, 463.

[116] Barnham, K. J.; Guo, Z. J.; Sadler, P. J. J. Chem. Soc., DaltonTrans. 1996, 2867.

[117] Teuben, J. M.; van Boom, S. S. G. E.; Reedijk, J. J. Chem. Soc.Dalton Trans. 1997, 3979.

[118] Djuran, M. I.; Milinkovic, S. U.; Bugarcic, Z. D.J. Coord. Chem.1998, 44, 289.

[119] Frhling, C. D. W.; Sheldrick, W. S. Chem. Commun. 1997, 1737.

[120] Hahn, M.; Wolters, D.; Sheldrick, W. S.; Hulsbergen, F. B.; Re-edijk, J.J. Biol. Inorg. Chem. 1999, 4, 412.

[121] Deubel, D. V.J. Am. Chem. Soc.2004, 126, 5999.[122] Bose, R. N.; Ghosh, S. K.; Moghaddas, S.J. Inorg. Biochem.1997,

65, 199.

[123] Ishida, S.; Lee, J.; Thiele, D. J.; Herskowitz, I. Proc. Natl. Acad.Sci. USA 2002, 99, 14298.

[124] Volckova, E.; Dudones, L. P.; Bose, R. N. Pharm. Res. 2002, 19,124.

[125] Pattanaik, A.; Bachowski, G.; Laib, J. J. Biol. Chem. 1992, 267,16121.

[126] Sasada, T.; Iwata, S.; Sato, N.; Kitaoka, Y.; Hirota, K.; Nakamura,K.; Nishiyama, A.; Taniguchi, Y.; Takabayashi, A.; Yodoi, J. J.Clin. Invest. 1996, 97, 2268.

[127] Murdoch, P. del S.; Kratochwil, N. A.; Parkinson, J. A.; Patriarca,M.; Sadler, P. J.Angew. Chem. Int. Ed. 1999, 38, 2949.

[128] Oehlsen, M. E; Qu, Y.; Farrell, N.Inorg. Chem.2003, 42, 5498.

[129] El-Khateeb, M.; Appleton, T. G.; Gahan, L.; Charles, B.; Berners-Price, S. J.; Bolton, A.J. Biol. Inorg. Chem. 1999, 77, 13.

[130] Jansen, B. A.; Brouwer, J.; Reedijk, J.J. Inorg. Biochem. 2002, 89,197.

[131] Ishikawa, T.; Ali-Osman. F.J. Biol. Chem.1993, 268, 20116.

[132] Mistry, P.; Loh, S. Y.; Kelland, L. R.Int. J. Cancer1993, 55, 849.

[133] Murdoch, P. del S.; Kratochwil, N. A.; Parkinson, J. A.; Patriarca,M.; Sadler, P. J.Angew. Chem. Int. Ed.1999, 38, 2949.

[134] Miao, R.; Yang, G. H.; Miao, Y.; Mei, Y. H.; Hong, J.; Zhao, C.M.; Zhu, L. G.Rapid Commun. Mass Spectrom. 2005, 19, 1031.

[135] Berners-Price, S. J.; Kuchel, P. W. J. Inorg. Biochem. 1990, 38,327.

[136] Berners-Price, S. J.; Kuchel, P. W. J. Inorg. Biochem. 1990, 38,305.

[137] Liu, Q.; Wei, H. Y.; Lin, J.; Zhu, L. G.; Guo, Z. J. J. Inorg.Biochem.2004, 98, 702.

[138] Wei, H. Y.; Liu, Q.; Lin, J.; Jiang, P. J.; Guo, Z. J. Inorg. Chem.Commun.2004,7, 792.

[139] Ishikawa, T.; Li, Z.-S.; Lu, Y.-P.; Rea, P. A.Biosci. Rep.1997, 17,189.

[140] Perez, R.; Johnson, S.; Handel, L.; ODwyer, P.; Hamilton, T.Gynecol Oncol.1995, 58, 312.

[141] Ishikawa, T.; Wright, C. D.; Ishizuka, H.J. Biol. Chem.1994, 269,29085.

[142] Cohen, S. M.; Lippard, S. J. Prog. Nucleic Acid. Res. Mol. Biol.2001, 67, 93.

[143] Ishikawa, T. Trends Biochem. Sci.1992, 17, 463.

[144] Lai, G.-M.; Ozols, R. F.; Young, R. C.; Hamilton, T. C.Biochem.Pharmacol.1989, 37, 4597.

[145] Chen, G.; Zeller, W.Anticancer Res.1991, 11, 2231.

[146] ODwyer, P.; Hamilton, T.; Young, R.; LaCreta, F.P.; Carp, N.;Tew, K.D.; Padavic, K.; Comis, R.L.;Ozols, R.F. J. Natl. CancerInst. 1992, 84, 264.

[147] Billings, P. C.; Davis, R. J.; Engelsberg, B. N.; Skov, K. A.;Hughes, E. N.Biochem. Biophys. Res. Comm.1992, 188, 1286.

[148] Bergelson, S.; Pinkus, R.; Daniel, V. Cancer Res.1994, 54, 36.[149] Potapova, O.; Haghighi, A.; Bost, F.; Potapova, O.; Haghighi, A.;

Bost, F.; Liu, C.; Birrer, M.J.; Gjerset, R.; Mercola, D. J. Biol.Chem. 1997, 272, 14041.

[150] Xia, Z.; Dickens, M.; Raingeaud, J.; Davis, R. J.; Greenberg, M. E.Science 1995, 270, 1326.

[151] Bose, R.N.; Moghaddes, S.; Weaver, E.L.; Cox, E.H.Inorg. Chem.1995, 34, 5878.

[152] Peleg-Shulman, T.; Gibson, D.J. Am. Chem. Soc. 2001, 123,3171.

[153] Teuben, J. M.; Zubiri, M. R.; Reedijk, J. J. Chem. Soc., DaltonTrans.2000, 369.


14/16


[154] Djuran, M. I.; Dimitrijevic, D. P.; Milinkovic, S. U.; Bugarcic, Z.D. Transition Metal Chem.2002, 27, 155.

[155] Marchan, V.; Moreno, V.; Pedroso, E.; Grandas, A. Chem. Eur. J.2001, 7, 808.

[156] Lau, J. K. -C.; Deubel, D. V. Chem. Eur. J.2005, 11, 2849.

[157] Siddik, Z. H. Oncogene2003, 22, 7265.

[158] Wernyj, R. P.; Morin, P. J.Drug Resist. Updates2004, 7, 227.

[159] Torigoe, T.; Izumi, H.; Ishiguchi, H.; Yoshida, Y.; Tanabe, M.;Yoshida, T.; Igarashi, T.; Niina, I.; Wakasugi, T.; Imaizumi, T.;Momii, Y.; Kuwano, M.; Kohno, K. Curr. Med. Chem. Anticancer

Agents2005, 5, 15.[160] Johnson, S. W.; Ferry, K. V.; Hamilton, T. C.Drug Resist. Updates

1998, 1, 243.

[161] Kartalou, M.; Essigmann, J. M.Mutat. Res. 2001, 478, 23.

[162] Sve, P.; Dumontet, C. Curr. Med. Chem. Anticancer Agents, 2005,5, 73.

[163] Bernareggi, A.; Torti, L.; Facino, R. M.; Carini, M.; Depta, G.;Casetta, B.; Farrell, N.; Spadacini, S; Ceserani, R.; Tognella, S. J.Chromatogr. B, 1995, 669, 247.

[164] Fuertes, M. A.; Castilla, J.; Alonso, C.; Prez, J. M. Curr. Med.Chem. Anticancer Agents 2002, 2, 539.

[165] Eastman, A. Chem. Biol. Interact.1987, 61, 241.

[166] Boulikas, T.; Vougiouka M. Oncol. Rep.2003, 10, 1663.

[167] Chen, Z. -S.; Mutoh, M.; Sumizawa, T.; Furukawa, T.; Haraguchi,M.; Tani, A.; Saijo, N.; Kondo, T.; Akiyama, S.-I. Exp. Cell Res.1998, 240, 312.

[168] Brabec, V.; Kasparkova, J.Drug Resist. Updates2002,5, 147.

[169] Ahn, H.; Lee, E.; Kim, K.; Lee, C.J. Urol.1994, 151, 263.[170] Pendyala, L.; Velagapudi, S.; Toth, K.; Pendyala, L.; Velagapudi,

S.; Toth, K.; Zdanowicz, J.; Glaves, D.; Slocum, H.; Perez, R.;Huben, R.; Creaven, P.J.; Raghavan, D. Clin. Cancer Res.1997, 3,793.

[171] Mistry, P.; Kelland, L. R.; Abel, G.; Sidhar, S.; Harrap, K. R.Br. J.Cancer1991, 64, 215.

[172] Britten, R. A.; Green, J. A.; Warenius, H. M. Int. J. RadiationOncol. Biol. Phys.1992, 24, 527.

[173] Salinas, A. E.; Wong, M. G. Curr. Med. Chem. 1999, 6, 279.

[174] Tew, K. D. Cancer Res. 1994, 54, 4313.

[175] McLellan, L. I.; Wolf, C. R.Drug Resist. Update1999,2, 153.

[176] Iida, T.; Mori, E.; Mori, K.; Goto, S;. Urata, Y.; Oka, M.; Kohno,S.; Kondo, T.Int. J. Cancer1999, 82, 405.

[177] Cullen, K. J.; Newkirk, K. A.; Schumaker, L. M.; Aldosari, N.;Rone, J. D.; Haddad, B. R. Cancer Res.2003, 63, 8097.

[178] Wang, W.; Ballatori, N. Pharmacol. Rev. 1998, 50, 335.

[179] Kelland, L. R.Drugs 2000, 59 (Suppl 4), 1.

[180] Garca-Ruz, C.; Mari, M.; Morales, A.; Colell, A.; Ardite, E.;Fernndez-Checa, J. C.Hepatology 2000, 32, 56.

[181] Holford, J.; Beale, P. J.; Boxall, F. E.; Sharp, S. Y.; Kelland, L. R.Eur. J. Cancer2000, 36, 1984.

[182] Pattanaik, A.; Bachowski, G.; Laib, J.; Lemkuil, D.; Shaw, C. F.,III; Petering, D. H.; Hitchcock, A.; Saryan, L. J. Biol. Chem.1992,267, 16121.

[183] Xing, B.; Zhu, H.; Shi, Y.; Tang, W.BioMetals2001, 14, 51.

[184] Hagrman, D.; Goodisman, J.; Dabrowiak, J. C.; Souid, A.-K.DrugMetab. Dispos.2003, 31, 916.

[185] Okasaki, Y.; Miura, N.; Satoh, M.; Imura, N.; Naganuma, A. Bio-chem. Biophys. Res. Commun.1998, 245, 815.

[186] Kasahara, K.; Fujiwara, Y.; Nishio, K.; Ohmori, T.; Sugimoto, Y.;Komiya, K.; Matsuda, T.; Saijo, N. Cancer Res.1991, 51, 3237.

[187] Kondo, Y.; Woo, E. S.; Michalska, A. E.; Choo, K. H.; Lazo, J. S.

Cancer Res.1995, 55, 2021.[188] Demachki, S.; Bacchi, C. E.J. Bras. Patol.1998, 34, 48.

[189] Jasani, B.; Schmid, K. W.Histopathology1997, 31, 211.

[190] Schilder, R. J.; Hall, L.; Monks, A.Int. J. Cancer1990, 45, 416.

[191] Saga,Y.; Hashimoto, H.; Yachiku, S.; Iwata, T.; Tokumitsu, M.Int.J. Urology2004, 11, 407.

[192] Arner, E. S. J.; Nakamura, H.; Sasada, T.; Yodoi, J.; Holmgren, A.;Spyrou, G. Free Radic. Biol. Med.2001, 31, 1170.

[193] Arnold, N. B.; Ketterer, K.; Kleeff, J.; Friess, H.; Buchler, M. W.;Korc, M. Cancer Res.2004, 64, 3599.

[194] Takeda, K.; Matsuzawa, A.; Nishitoh, H.; Ichijo, H. Cell Struct.Funct.2003, 28, 23.

[195] Chung, Y. M.; Yoo, Y. D.; Park, J. K.; Kim, Y. T.; Kim, H. J.Anticancer Res.2001, 21, 1129.

[196] Levi, J.; Jacobs, C.; Kalman, S. M.; McTigue, M.; Weiner, M. W.J. Pharmacol. Exp. Ther.1980, 213, 545.

[197] Weiner, M. W.; Jacobs, C. Fed. Proc.1983, 42, 2974.

[198] Uozumi, J.; Litterst, C. L. Cancer Chemother. Pharmacol. 1985,15, 93.

[199] Kim, Y. K.; Byun, H. S.; Kim, Y. H.; Woo, J. S.; Lee, S. H. Toxi-

col. Appl. Pharmacol.1995, 130, 19.[200] Kruidering, M.; van de Water, B.; de Heer, E.; Mulder, G. J.;

Nagelkerke, J. F.J. Pharmacol. Exp. Ther.1997, 280, 638.

[201] Somani, S. M.; Ravi, R.; Rybak, L. P. Drug Chem. Toxicol.1995,18, 151.

[202] Zhang J. G.; Lindup, W. E. Pharmacol. Toxicol.1996, 79, 191.

[203] Husain, K.; Morris, C.; Whitworth, C.; Trammel, G. L.; Rybak, L.P.; Somani, S. M. Fund. Appl. Toxicol, 1996, 32, 278.

[204] Zhang, L.; Hanigan, M. H. J. Pharmacol. Exp. Ther. 2003, 306,988.

[205] Townsend, D. M.; Marto, J. A.; Deng, M.; Macdonald, T. J.; Hani-gan, M. H.Drug Metab. Dispos.2003, 31, 705.

[206] Hanigan, M. H.; Frierson, H. F.; Swanson, P. E.; De Young, B. R.Hum. Pathol.1999, 30, 300.

[207] Daubeuf, S.; Balin, D.; Leroy, P.; Visvikis, A. Biochem. Pharma-col.2003, 66, 595.

[208] Hanigan, M. H.; Lykissa, E. D.; Townsend, D. M.; Ou, C.-N.;

Barrios, R.; Lieberman, M. W.Am. J. Pathol.2001, 159, 1889.[209] Paolicchi, A.; Sotiropuolou, M.; Perego, P.; Daubeuf, S.; Visvikis,

A.; Lorenzini, E.; Franzini, M.; Romiti, N.; Chieli, E.; Leone, R.;Apostoli, P.; Colangelo, D.; Zunino, F.; Pompella, A. Eur. J. Can-cer2003, 39, 996.

[210] Townsend, D. M.; Hanigan, M. H.J. Pharmacol. Exp. Ther.2002,300, 142.

[211] Townsend, D. M.; Deng, M.; Zhang, L.; Lapus, M. G.; Hanigan,M. H.J. Am. Soc. Nephrol.2003, 14, 1.

[212] Pasini, A.; Moroni, M.J. Chem. Soc., Dalton Trans. 1997, 1093.

[213] Chen, Y.; Guo, Z.; del S. Murdoch, P.; Zang, E.; Sadler, P. J.J.Chem. Soc. Dalton Trans.1998,1503.

[214] Kovacs, A. F.; Cinatl, J.J. Cranio-Maxillofacial Surgery2002, 30,54.

[215] Bergstrom, P.; Johnsson, A.; Bergenheim, T.; Henriksson, R. J.Neuro-Oncol.1999, 42, 13.

[216] Potdevin, S.; Courjault-Gautier, F.; Du Sorbier, B. M.; Ripoche, P.;

Toutain, H. J.J. Pharmacol. Exp. Ther.1998, 284, 142.[217] Hausheer, F. H.; Kochat, H.; Parker, A. R.; Ding, D.; Yao, S.;

Hamilton, S. E.; Petluru, P. N.; Leverett, B. D.; Bain, S. H.; Saxe,J. D. Cancer Chemother. Pharmacol. 2003, 52, S3.

[218] Smyth, J. F.; Bowman, A.; Perren, T.; Wilkinson, P.; Prescott, R.J.; Quinn, K. J.; Tedeschi, M.Ann. Oncol.1997, 8, 569.

[219] Mishima, K.; Hidaka, S.; Takamura, N.; Shinozawa, S.Renal Fail-ure1999, 21, 593.

[220] Sha, S. H.; Schacht, J.Hearing Res.2000, 142, 34.

[221] Krning, R.; Lichtenstein, A. K.; Nagami, G. T. Cancer Che-mother. Pharmacol.2000, 45, 43.

[222] Feghali, J. G.; Liu, W.; Van de Water, T. R. Laryngoscope2001,111, 1147.

[223] Dickey, D. T.; Muldoon, L. L.; Kraemer, D. F.; Neuwelt, E. A.Hearing Res.2004, 193, 25.

[224] Markman, M. Semin. Oncol.1998, 25, 522.

[225] Philips, K. A.; Tannock, I. F.J. Clin. Oncol.

1998

,16

, 3179.[226] Culy, C. R.; Spencer, C. M.Drugs2001, 61, 641.

[227] Korst, A. E. C.; Boven, E.; van der Sterre, M. L. T.; Fichtinger-Schepman, A. M. J.; van der Vijgh, W. J. F. Eur. J. Cancer1998,34, 412.

[228] Castiglione, F.; Dalla Mola, A.; Porcile, G. Tumori1999, 85, 85.

[229] Church, M. W.; Blakley, B. W.; Burgio, D. L.; Gupta, A. K. JARO-J. Assoc. Res. Otolaryngol.2004, 5, 227.

[230] Mori, T.; Nikaido, O.; Sugahara, T. Int. J. Radiat. Oncol. Biol.Phys. 1984, 10, 1529.


15/16


[231] Treskes, M.; van der Vijgh, W. J. F. Cancer Chemother. Pharma-col.1993, 33, 93.

[232] Capizzi, R. L. Semin. Oncol. 1999, 26(Suppl 7), 3.

[233] Giatromanolaki, A.; Sivridis, E.; Maltezos, E.; Koukourakis, M. I.Semin. Oncol.2002, 29(Suppl 19), 14.

[234] Treskes, M.; Nijtmans, L.; Fichtinger-Schepman, A. M. J.; van derVijgh, W. J. F.Anticancer Res. 1992, 12, 2261.

[235] Treskes, M.; Holwerda, U.; Nijtmans, L. G. J.; Pinedo, H. M.; vander Vijgh, W. J. F. Cancer Chemother. Pharmacol.1992, 29, 467.

[236] Souid, A.-K.; Fahey, R. C.; Aktas, M. K.; Sayin, O. A.; Karjoo, S.;

Newton, G. L.; Sadowitz, P. D.; Dubowy, R.L.; Berstein, M. L.Drug Metab. Dispos.2001, 29, 1460.

[237] Tacka, K. A.; Dabrowiak, J. C.; Goodisman, J.; Souid, A.-K.DrugMetab. Dispos.2002, 30, 875.

[238] Treskes, M.; Holwerda, U.; Klein, I.; Pinedo, H. M.; van der Vijgh,W. J. F.Biochem. Pharmacol. 1991, 42, 2125.

[239] Thompson, D. C.; Wyrick, S. D.; Holbrook, D. J.; Chaney, S. G.Cancer Res. 1995, 55, 2837.

[240] Treskes, M.; L. Nijtmans, G. J.; Fichtinger-Schepman, A. M. J.;van der Vijgh, W. J. F.Biochem. Pharmacol. 1992a, 43, 1013.

[241] Sadowitz, P. D.; Hubbard, B. A.; Dabrowiak, J. C.; Goodisman, J.;Tacka, K. A.; Aktas, M. K.; Cunningham, M. J.; Dubowy, R. L.;Souid, A.-K.Drug Metab. Dispos. 2002, 30, 183.

[242] Korst, A. E. C.; van der Sterre, M. L. T.; Gall, H. E.; Fichtinger-Schepman, A. M. J.; Vermorken, J. B.; van der Vijgh, W. J. F.Clin. Cancer Res. 1998, 4, 331.

[243] Doz, F.; Berens, M. E.; Spencer, D. R.; Dougherty, D. V.; Rosen-

blum, M. L. Cancer Chemother. Pharmacol. 1991, 28, 308.[244] Pierelli, L.; Scambia, G.; Fattorossi, A.; Bonanno, G.; Battaglia, A.;

Perillo, A.; Menichella, G.; Panici, P. B.; Leone, G.; Mancuso, C.Br. J. Cancer1998, 78, 1024.

[245] Verstappen, C. C.; Geldof, A. A.; Postma, T. J.; Heimans, J. J.J.Neuro-Oncol.1999, 44, 1.

[246] Shaw, L. M.; Bonner, H. S.; Brown, D. Q.Drug Metab. Dispos.1994, 22, 895.

[247] Treskes, M.; Boven, E.; Holwerda, U.; Pinedo, H. M.; van derVijgh, W. J. F. Cancer Res.1992, 52, 2257.

[248] Bergstrm, P.; Johnsson, A.; Bergenheim, T.; Hendriksson, R. J.Neuro-Oncol.1999, 42, 13.

[249] van Laar, J. A. M.; van der Wilt, C. L; Treskes, M.; van der Vijgh,W. J. F.; Peters, G. J. Cancer Chemother. Pharmacol. 1992, 31, 97.

[250] Treskes, M.; Boven, E.; van de Loosdrecht, A. A.; Wijffels, J. F. A.M.; Cloos, J.; Peters, G. J.; Pinedo, H. M.; van der Vijgh, W. J. F.Eur. J. Cancer1994, 30A, 183.

[251] Mollman, J. E.; Glover, D. J.; Hogan, W. M.; Furman, R. E. Can-cer1988, 61, 2192.

[252] Hartmann, J. T.; Fels, L. M.; Knop, S.; Stolte, H.; Kanz, L.;Bokemeyer, C.Invest. New Drugs2000, 18, 281.

[253] Rubin, J. S.; Wadler, S.; Beitler, J. J.; Haynes, H.; Rozenblit, A.;McGill, F.; Goldberg, G.; Runowicz, C. J. Laryngol. Otolog.1995,109, 744.

[254] Betticher, D. C.; Anderson, H.; Ranson, M.; Meely, K.; Oster, W.;Thatcher, N.Br. J. Cancer1995, 72, 1551.

[255] Budd, G. T.; Ganapathi, R.; Adelstein, D. J.; Pelley, R.; Olenchi,T.; Petrus, J.; Mclain, D.; Zhang, J.; Capizzi, R.; Bukowski, R. M.Cancer1997, 80, 1134.

[256] Hartmann, J. T.; von Vangerow, A.; Fels, L. M.; Knop, S.; Stolte,H.; Kanz, L.; Bokemeyer, C.Br. J. Cancer2001, 84, 313.

[257] Glover, D.; Grabelsky, S.; Fox, K.; Weiler, C.; Cannon, L.; Glick,J.Int. J. Radiat. Oncol. Biol. Phys. 1989, 16, 1201.

[258] Budd, G. T.; Ganapathi, R.; Bauer, L.; Murthy, S.; Adelstein, D.;

Weick, J.; Gibson, V.; McLain, D.; Sergi, J.; Bukowski, R. M.;Eur. J. Cancer1993, 29A, 1122.

[259] Glover, D.; Glick, J. H.; Weiler, C.; Fox, K.; Guerry, D.J. Clin.Oncol.1987, 5, 574.

[260] Ekborn, A.; Hansson, J.; Ehrsson, H.; Eksborg, S.; Wallin, I.;Wagenius, G.; Laurell, G.Laryngoscope2004, 114, 1660.

[261] Korst, A. E. C.; Boven, E.; van der Sterre, M. L. T.; Fichtinger-Schepman, A. M. J.; van der Vijgh, W. J. F. Br. J. Cancer1997,75, 1439.

[262] Sadowitz, P. D.; Hubbard, B. A.; Dabrowiak, J. C.; Goodisman, J.;Tacka, K. A.; Aktas, M. K.; Cunningham, M. J.; Dubowy, R. L.;Souid, A.-K.Drug Metab. Dispos. 2002, 30, 183.

[263] Romero, F. J.; Segura-Aguilar, J.; Monsalve, E.; Hermenegildo, C.;Nies, E.; Puertas, F. J.; Roma, J. Neurotoxicol. Teratol. 1990, 12,603.

[264] Paolicchi, A.; Sotiropolou, M.; Perego, P.; Daubeuf, S.; Visvikis,A.; Lorenzini, E.; Franzini, M.; Romiti, N.; Chieli, E.; Leone, R.;Apostoli, P.; Colangelo, D.; Zunino, F.; Pompella, A.; Eur. J. Can-cer2003, 39, 996.

[265] Hogarth, L.; English, M.; Price, L.; Wyllie, R.; Pearson, A. D. J.;Hall, A. G. Cancer Chemother. Pharmacol.1996, 37, 479.

[266] Paolicchi, A.; Lorenzini, E.; Perego, P.; Supino, R.; Zunino, F.;Comporti, M.; Pompella, A.Int. J. Cancer2002, 97, 740.

[267] Hanada, K.; Mukasa, Y.; Nomizo, Y.; Ogata, H. J. Pharm. Phar-macol.2000, 52, 1483.

[268] Hamers, F. P.; Brakkee, J. H.; Cavalletti, E.; Tedeschi, M.; Mar-monti, L.; Pezzoni, G.; Neijt, J. P.; Gispen, W. H. Cancer Res.1993, 53, 544.

[269] Cavaletti, G.; Minoia, C.; Schieppati, M.; Tredici, G.Int. J. Radiat.Oncol. Biol. Phys.1994, 29, 771.

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