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

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The Role of Sulfur in Platinum Anticancer Chemotherapy

Xiaoyong Wang1 and Zijian Guo2,*
1

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, 210093, Nanjing P.R.China and 2State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemistry and Chemical Engineering, Nanjing University, 210093, Nanjing, P.R. China
Abstract: Sulfur manifests its influence on platinum anticancer chemotherapy in two aspects: endogenous sulfurcontaining 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 platinumsulfur 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 design of new generation of platinum-based anticancer drugs.

Key Words : Anticancer drug, Platinum complex, Sulfur, Platinum-sulfur interaction, Chemotherapy, Chemoprotectant, Resistance, Sulfur-containing molecules. INTRODUCTION Sulfur-containing biomolecules such as cysteine (Cys), methionine (Met), glutathione (GSH), metallothionein (MT) and albumin play significant roles in platinum anticancer chemotherapy 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 cell uptake, deactivation prior to DNA binding, and formation of DNA-adduct, etc [4]. The nature of the final products for most of these reactions has been clarified [4-6]. However, the role of sulfur compounds has been controversial. On one hand, the interactions between sulfur-containing molecules and platinum drugs are considered to have negative effects on the therapeutic efficacy of the drugs [2, 7-9]. For example, they have been related to drug detoxification, nephrotoxicity and resistance [10, 11]; strong and irreversible binding of cisplatin to intracellular thiolate ligands such as GSH and Cys-rich MTs has been considered as a major inactivation step for this drug [12-14]; and reactions of platinum drugs with sulfur donors in peptides and proteins are believed to alter the conformation of proteins and lead to changes in biological activity, especially when enzymatic reactions are affected [15]. On the other hand, the platinumsulfur interactions can be used to produce favorable effects in the clinical application of Pt-based drugs. It is possible now to employ sulfur-containing compounds as chemoprotectants to mitigate the severe toxic side effects of platinum drugs and some of them have been registered in a number of European countries [16-18]. Moreover, the design of new generations of platinum-based drugs can be benefited from the understanding of these interactions.
*Address correspondence to this author at the State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P.R. China; Fax: +86-25-83314502; E-mail: zguo@nju.edu.cn 1871-5206/07 $50.00+.00

Most of the sulfur-containing molecules to be discussed in this review are endogenous compounds found in human body and only those compounds taken in for protective or therapeutic purposes are alien synthetics. According to the origins of these molecules, this review is arranged in two parts: endo-sulfur and exo-sulfur. The first part deals with the natural sulfur-containing molecules that may potentially influence the efficacy of the platinum drugs and the second part concerns the synthetic compounds that may protect the normal cells from the damage of these drugs. Since many valuable reviews on this subject have appeared over the years [2, 19-21], this review will concentrate only on the most recent advances in this area. ENDO-SULFUR A. Endogenous Sulfur-containing Molecules in Human Body Sulfur Containing Amino Acids Sulfur containing amino acids play important roles in maintaining the integrity of cellular systems by influencing the cellular redox state and the capacity to detoxify toxic compounds, free radicals and reactive oxygen species. Methionine (Met) and cysteine (Cys) are the two principal sulfur-containing amino acids in mammals. Both of them contribute significantly to the cellular pool of organic sulfur and to the sulfur homeostasis as well as to the regulation of one carbon metabolism. Met is an essential amino acid provided by the diet and the de novo recycling of homocysteine (Hcy) [22]. Apart from its role in protein synthesis, Met is the substrate for the formation of S-adenosylmethionine (AdoMet), the widely utilized methyl donor for DNA, protein and lipid methylations [23]. A broad range of cancer cell lines have been characterized by their dependence on Met [24], which is defined by the inability to grow in a Met-depleted environment sup 2007 Bentham Science Publishers Ltd.

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plemented with Hcy. In contrast, normal cells are able to efficiently utilize Hcy and sustain growth in the absence of externally provided Met [25, 26]. This feature offers the possibility to control selectively the proliferation of Metdependent cancer cells by depleting Met and the potential to devise a specific and selective therapeutic strategy [27]. Different from Met, the essential amino acid Cys is provided by the diet as a metabolite of Met or obtained from tissues expressing the enzymes of the trans-sulfuration. Cys takes 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 significant role in one carbon metabolism and methylation reactions. The only source of Hcy in human body is from the demethylation of dietary Met. Hcy can be remethylated to form Met again with the aid of Met synthase. In most tissues, the remethylation of Hcy is dependent on the cofactor activity of folate and Vitamin B12. Hcy can also be metabolized through transsulfuration to produce Cys with the aid of Vitamin 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 as cardiovascular disease [33-35]. A comprehensive review on sulfur-containing amino acids and human disease has appeared recently, which should provide more information for readers who are interested in this subject [36]. Sulfur Containing Peptide and Proteins Glutathione (GSH, 1) is a water-soluble tripeptide composed of glutamate (Glu), cysteine (Cys) and glycine (Gly). With its intracellular content about 0.510 mM1 [1, 37, 38], GSH is one of the most abundant non-protein thiols in cells. GSH contains an unusual -peptide bond between glutamate and cysteine, which prevents GSH from being hydrolyzed by most peptidases. Intracellular GSH is kept in its thiol form by GSH disulfide reductase, a NADPH-dependent enzyme, and hence the mercapto group in GSH is a potent reducing agent. The maintenance of a reduced cellular environment is greatly dependent on the maintenance of a balanced redox potential by GSH. As a primary source of cellular nucleophiles and an important antioxidant, GSH plays a key role in the detoxification of a variety of electrophilic compounds and peroxides under catalysis of glutathione S-transferases (GST) and glutathione peroxidases (GPx) [39]. GSH has various physiological functions in cellular defense and

metabolism, including modulation of thiol-disulfide status of cellular proteins, protection of cells from oxidative stress, synthesis and transport of biologically active endogenous substances, detoxification and/or bioactivation of drugs [4042]. The importance of GSH in human disease has been reviewed recently [39], thus details in this respect are omitted here.
SH COOH NH2 CH CH2 CH2 O C CH2 O NH CH 1 C NH CH2COOH

Albumin is the most abundant protein in blood plasma, amounting to ca 52% of its proteic composition and presenting in concentrations of 40 mg ml-1 (~ 0.6 mM; Mr = 66 kDa) in normal individuals [43]. Human serum albumin (HSA) consists of a single chain of 585 amino acids organized in three structurally homologous domains (I, II and III), each of them contains two sub-domains [44]. The threedimensional structure of HSA has been intensively studied [45]. At physiological pH, albumin presents two structural isomers, 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 osmotic blood pressure, the transport, metabolism and distribution of endogenous or exogenous substances such as hormones, amino acids, fatty acids, metal cations and drugs, deactivation of free radicals in the extracellular medium, and the source of amino acids for protein synthesis after hydrolysis [44, 46, 47]. Metallothionein (MT) is a thiol-rich protein found in all eukaryotes and some prokaryotes and has been studied extensively since its discovery in 1957. MT constitutes a family of low molecular weight intracellular metalloproteins that have been subdivided into three classes, i.e. MT-I, MT-II, and MT-III [48]. Mammalian MTs, mostly belonging to MTI, are composed of a string of 61 or 62 amino acids, 20 of which are conserved Cys residues. These proteins are able to bind up to seven divalent atoms, mainly metals, and other compounds, such as free radicals [49]. The metal binding to the thiol group of Cys residues is very strong, and is dynamically controlled by the oxidoreductive environment of the

CH3

COOH H NH2 Met Met synthase folate, VB12

HS

COOH cystathionine -synthase H NH2 Hcy VB6

HS

COOH H NH2 Cys

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

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

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

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to play important physiological roles in the metabolism and storage of essential trace metals as well as in the detoxification of toxic metals such as sequestering Cd2+, Hg2+, Au+, and Pt 2+ ions [55-57], and thereby prevent them from reacting with other cellular targets. The physiological or pharmacological functions of MTs could also be extended to the scavenging of radicals, response to stresses, and effectiveness 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 protein with a single polypeptide chain of 679 amino acids, including 9 Met residues and 37 Cys residues (vide infra), and a molecular weight of ca. 80 kDa. The single chain has two similar lobes (N- and C-lobe) connected by a short peptide. Each lobe can be further divided into two domains of similar size, which have alternating -helical and -sheet segments. In human serum, the concentration of transferrin is about 2.5 mg/ml (35 M) with 30% occupied with iron [60]. The fundamental role of transferrin is the binding and transporting of non-heme iron into the cell via receptor mediated endocytosis [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 of metal 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 biomedical processes are skipped here for they have been summarized in several reviews recently [61, 64-66].

B. Interactions of Platinum Drugs with Sulfur-containing Molecules The platinum-sulfur interaction is a complicated issue because of the great abundance and vast distribution of sulfur-containing biomolecules in human body. These interactions may occur inside or outside of the cells and are directly related to the metabolism, toxicity and resistance of platinum-based drugs. It is commonly believed that platinum drugs exert their antitumoral effect primarily by interacting with cellular DNA [67, 68]. However, on their way to the DNA target, platinum drugs will inevitably meet a variety of sulfur-containing molecules. Only those platinum species that have successfully escaped the hijacking of sulfurcontaining molecules could finally bind to DNA and lead to the death of the dividing cells [69-71]. Some of the major interactions of platinum drugs with sulfur-containing biomolecules are summarized in Fig. (2). With Extracellular Sulfur-containing Molecules Human serum albumin (HSA) is the most abundant plasma protein and any injected metal drug should have some kind of interaction with this macromolecule, which could crucially determine its bioavailability and toxicology. Without exception, platinum-based drugs also bind to HSA and such reactions may be related to the metabolism, efficacy, and body distribution of the drugs [72, 73]. In fact, there is about 6598% of cisplatin in blood binds quasi irreversibly to HSA, which brings cisplatin in circulation. The major platinum binding sites in HSA appears to be Met rather 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 residue and thus has been speculated to be the main cisplatin-binding site. The other exposed residues are Met87 and Met446. These residues may be involved in the formation of monofunctional adducts or S,N-macrochelates with cisplatin [75]. The polypeptide amide, carbonyl and sulfur donor groups could be additional platinum binding sites in HAS, which has been proposed based on FTIR experiments [76]. The kinetic studies of cisplatin with albumin in a simulated biological system revealed that cisplatin binding to the protein obeyed a S N2 mechanism [72]. The apparent pseudofirst-order rate constant kapp correlated linearly with [albumin]: kapp = 0.263 + 0.405[albumin] Antitumor platinum(II) complexes other than cisplatin have been studied in different animal models for their pharmacokinetics (Fig. (3)). Oxaliplatin exhibited similar [77] or greater protein binding ability than cisplatin [78] or carboplatin [79]. In human plasma, albumin and -globulins shared similar levels of oxaliplatin within 3 h after i.v. administration [80]; and equilibrium between oxaliplatin and albumin alone or total plasma was attained after 24 and 5-6 h, respectively, with 7987% of the Pt covalently bound to purified albumin [81]. However, other recently approved platinum-based drugs such as nedaplatin [82] and lobaplatin [83] (Fig. (3)) showed poor association with plasma proteins. Although the quasi irreversible albumin-cisplatin binding was once suggested not to constitute a drug reservoir for therapeutic purposes, a number of studies showed evidence of positive clinical effects of this adduct. For example, both free and protein-bound cisplatin exhibit similar effects in seven tumor models [84]; administration of cisplatin-HAS increases tumor concentration of Pt [85]; and treatment with three courses of the adduct leads to a complete remission of laryngeal carcinoma [86]. The chemotherapeutic effect of carboplatin could also be enhanced by albumin [87]. On the other hand, the response of hypoalbuminemic patients to cisplatin therapy is poor [88,89]. In addition, decreased plasma albumin levels increase marrow, nefro-, hepato- or oto-toxicity of cisplatin, as well as the drug levels in pregnant women and fetus [90-92]. A review chiefly discusses the interactions of platinum-based metallodrugs with albu-

min has been published recently [93], which should provide more general knowledge on this subject. The methionine (Met) residue of proteins is one of the primary target sites for platinum-based drugs. In the case of transferrin, there are 9 Met residues, i.e. Met26, 109, 256, 309, 313, 382, 389, 464, 499, and 37 Cys residues involved in 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 binding site, but its rate of platination is slower than that of Met256. When Pt(II) reacts with N-lobe alone, the binding occurs at Met313, which is buried in the interlobe contact region of intact transferrin. Transferrin may take cisplatin into the cells via transferrin receptor. With ca 146 nmol content per milligram of plasma protein, Met itself plays an important role in the metabolism of platinum anticancer drugs. A variety of biological effects are related to the interactions of platinum complexes with Met and its derivatives [96]. Therefore, extensive studies have been carried out on these interactions in order to understand their implications for the platinum chemotherapy. Methionine coordinates to platinum diamine compounds in different manners depending on the reactant and reaction conditions (Fig. (4)). The complex [Pt(Met-S,N)2] has been detected from the urine of patients treated with cisplatin over two decades ago [97], and its geometrical isomers have been separated and characterized [98]. Recent studies showed that the reaction of cisplatin with Met gave rise to the formation of 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 metabolite [Pt(Met- S,N)2] [99, 100]. The biological role of these adducts is unclear. Early studies found that the mono-Met substituted cisplatin was more nephrotoxic than aquated cisplatin species, but the specific Met-platinum adduct responsible for this nephrotoxicity was not identified [101, 102]. Met was shown to react rapidly with carboplatin to form long-lived ring-opened complexes, and the stable adduct [Pt(CBDCA-O)(NH3)2(Met-S)] has been characterized [103105]. Interestingly, a similar ring-opened complex has been detected in the urine of animals treated with carboplatin. Carboplatin was presumed to be a prodrug of cisplatin, but its aquation rate is too slow to account for its in vivo activity.

H3N Pt H3N

Cl Cl

H2 N Pt N H2

O O

O O

cisplatin

oxaliplatin H2 N Pt O nedaplatin N H2 O

O H3N Pt H3N O O carboplatin O

H3N Pt H3N

lobaplatin

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

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N Pt O O N+N3

N S O

N Pt H2N

N S

N Pt S

N S

O-

H3N+ O

OH3N+ O

O-

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

It is therefore postulated that Met may play a role in the activation of carboplatin [106]. The reactivity of Met with cisplatin, carboplatin and oxaliplatin has been compared with each other. Carboplatin and oxaliplatin show a different reactivity towards Met from that of cisplatin. Cisplatin in water is about 4.5-fold more reactive with Met than carboplatin [107]. This result is in good agreement with the early finding that cisplatin was more reactive 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 and carboplatin. The formation of mixed-ligand adducts as it is in the case of cisplatin and carboplatin is prevented in oxaliplatin due to the high stability of Pt(II)-DACH moiety. The discrepancy between the reactions with Met could partly explain the therapeutic differences of these drugs, and it could also provide clues for the presumed unique mode of action for oxaliplatin. A noteworthy feature for oxaliplatin is that Met has a major influence on its binding behavior to 5guanosine monophosphate (5-GMP) by competing with 5GMP for the platinum binding sites. The coordination of oxaliplatin with 5-GMP is inhibited and the Pt-bound 5GMP 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 the non-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 complexes may be potential intermediates for DNA platination [113115]. For example, when S-methylglutathione (GSMe) and 5-GMP were added to a solution of [Pt(dien)Cl]Cl (dien = diethylenetriamine), coordination of platinum to thioether occurred initially, but coordination to the N7 atom of 5GMP 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 reactants, where one of two sulfur-coordinated N-AcMet ligands could be replaced by 5-GMP [116]. Other experiments showed that the thioether sulfur-bound Met can be displaced from [Pt(dien)(Met-S)]+ intra- [117] or inter-molecularly [118] by guanine at physiological pH. The fact that an intramolecular migration of [Pt(dien)]2+ from a kinetically favoured Met to a thermodynamically preferred histidine (His) in different peptides such as His-Met [119], His-Gly-Met and Ac-His-Ala-Ala-Ala-Met-NHPh [120] suggests both kinetic and thermodynamic stability play important role when cisplatin binding to biological targets [121].

The reaction between L-Cys and cisplatin has been examined at neutral pH at 37 C [122]. The reaction proceeds through a [Pt(NH3)2(Cys)Cl] intermediate that is formed by a direct reaction of cisplatin with Cys. The intermediate undergoes parallel reactions with a second Cys to form a bis(Cys) complex [Pt(NH3)2(Cys)2] and with the starting cisplatin to form a Cys-bridged dinuclear complex. In the presence of excess Cys, the product is predominantly the bis(Cys) complex (Fig. ( 5)). The bis(Cys) complex at neutral pH 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 Cys was increased fourfold over cisplatin, the coordinated ammonia in [Pt(NH3)(Cys)2] was removed completely giving rise to the [Pt(Cys) 2] as the dominant product where two Cys act as S,N-chelating agents. These intermediates and products have been characterized by 195Pt and 15N NMR spectroscopy. However, the biological roles of these species are not reported so far. With Intracellular Sulfur-containing Molecules As shown in Fig. (2), cisplatin enters the cell from blood via passive diffusion or through metal transporters such as Met-rich copper transporter CTR1 [123]. After hydrolysis in cytosol, the active species of cisplatin enters the nuclear envelope and binds to DNA, which finally triggers cell-cycle arrest and apoptosis. However, intracellular sulfur-containing molecules such as GSH [124], MT [125] and thioredoxin [126] would compete for cisplatin with DNA. These reactions have been associated with the increased cisplatin resistance and inactivation. In fact, the efficacy of platinum-based anticancer agents is a balance between target efficiency (DNA binding) and metabolism by sulfur nucleophiles [127130]. The most important non-DNA target of cisplatin is probably GSH, which is present in cells at high concentrations [20]. In cytoplasm, a major fraction (ca 60%) of the intracellular cisplatin is conjugated with GSH, and only a small fraction of cisplatin can bind to DNA [131]. GSH reacts with cisplatin to form the Pt-GS complex that is active in the inhibition of cell-free protein synthesis; in the nucleus, GSH can quench DNA-platinum monoadducts before their conversion to the cross-linking bis-adducts [132]. The existence of PtGS complex both in a cell-free system and in murine leukemia L1210 cells has been confirmed via direct interaction between cisplatin and GSH with its molecular mass corresponding to chelate bis-(glutathionato)-platinum [131]. Other Pt-GS adducts have also been found via the interaction of cisplatin analogues and GSH [133-134]. The principal bind-

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Anti-Cancer Agents in Medicinal Chemistry, 2007, Vol. 7, No. 1 NH3+ + H S Cys H+ H3 N Cl

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Wang and Guo

H3N H3N

Pt

Cl Cl

COO-

cisplatin

k 1 = 0.022 M-1S- 1 S Cl COOk3 = 0.24 M- 1S-1 COOH3N H3N

3N

Cys

H3 N

Pt

Cl-

k 2 = 0.056 M-1S -1 +H3N COOH 3N H 3N Pt S S COO +H3N NH3 H 3N H 2N HOOC H2 N NH3 H2 N HOOC S Pt S S Pt S NH3+ HOOC COO-OOC -

+H3N cisplatin
3Cl +H

Pt

S N H2 Cys COOH

H3N H3N

Pt

S S

Pt

NH3 NH3 H3N S Pt

NH3 S N H2 COOH

NH3 + dimer +H3N COO

-

NH3 HOOC H2 N S

Pt

S N H2 COOH

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

ing modes in these adducts have been unambiguously identified as either monodentate Pt-GS or bridged Pt-GS-Pt [128, 135-138]. Formation of the Pt-GS complex plays a significant role in the cellular metabolism of cisplatin, because it reduces the amount of intracellular platinum available for interaction with DNA and protects dividing cells from cisplatin toxicity. The elimination of the Pt-GS complex from tumor cell may reduce the intracellular accumulation of the platinum complex [139]. The inverse correlation between GSH levels and cisplatin accumulation has been observed in spontaneously transformed rat ovarian surface epithelial cell lines [140]. The deactivated Pt-GS complex is believed to be exported by the GS-X pump [9, 131, 141, 142], which is an ATP-dependent export pump localized in the plasma membranes of different organs and cell types. This hypothesis is based on the transport activity and high affinity of GS-X pump toward GSH S-conjugates (GS-conjugates), GSH disulfide (GSSG), and cysteinyl leukotrienes [143]. Actually, one of the major functions of the GS-X pump is excretion and/or sequestration of toxic compounds in cellular protection system [139]. GSH can potentially affect cisplatin sensitivity in several ways. In addition to the formation of the deactivated Pt-GS complex, GSH could directly or indirectly participate in DNA repair. Inhibition of DNA repair in cisplatin-resistant human ovarian cancer cells has been achieved by depletion

of GSH with buthionine sulphoximine (BSO), a specific inhibitor of the GSH-synthetic enzyme -glutamyl Cys synthetase (-GCS) [144]; and enhancement of cisplatin cytotoxicity in several in vitro and in 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 the reduced 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 factors such as c-fos and c-jun that potentially affect DNA repair and apoptosis [148-150]. It was suggested that the reaction of hydrolyzed cisplatin derivatives with sulfur ligands gives a drug reservoir from which the Pt(II)-diammine moiety is slowly released to DNA and 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 complex is very stable. A study of competitive binding of Pt(II) complexes with GSH and 5-GMP showed that intermolecular displacement of S-bound deprotonated thiolate by the N7 atom of guanine is not possible [151, 152]. In addition, GSH can easily convert platinum-thioether adducts into thiolate adducts [153, 154], even replace the S, N-chelated L-Met from Pt(II) complex to form polynuclear Pt-GS adducts [137, 138]. The distinct thermodynamic and kinetic differences between the platinum-thiolates and platinum-thioethers may be important in the cellular processing of platinum-protein

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adducts [1, 153]. For instance, the substitution of platinumthioether to -thiolate is an important mechanism in the circumvention of cisplatin induced toxicity by thiol-containing protective agents (vide infra).
H3N Pt H3N GSH/Cys/Met binding H3N Pt H3N X S-ligand X OH2 DNA binding H3N Pt H3N X N7-Gua

release from drug reservoir ammine loss H3N Pt Y X S-ligand

Fig. (6). Intracellular competitive binding and inactivation of cisplatin 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 the intracellular inactivation of cisplatin is the displacement of one or both ammine ligands from the metal. There is strong evidence that GSH or Met residues in biomolecules can displace the ammine from cisplatin derivatives prior to DNA binding [12, 131, 155]. Recent theoretical studies indicate that after initial binding of cisplatin hydrolysis products to thioethers or thiols, loss of the ammine trans to this sulfur ligand rather than replacement of the sulfur ligand itself by other nucleophiles like guanine-N7 is predicted to be the predominant reaction [156]. These results would be helpful for understanding the real mode of cisplatin inactivation prior to DNA binding. C. Correlation between Drug Resistance and Sulfurcontaining Molecules The curative potential of platinum-based drugs is frequently undermined by the acquisition or presence of drug resistance. Multiple potential mechanisms of resistance have been identified at the cellular and molecular levels [20, 157159]. One of them is closely related to the inactivation of drugs by thiol-containing species such as metallothionein (MT), glutathione (GSH), and thioredoxin (Trx) [160-162], though direct interactions of cisplatin and GSH are negligible in blood because of the low contentrations of both molecules [163]. Intracellular inactivation of the cis-Pt(II) center by Cys residues of the cytoplasmic GSH or MT before binding to DNA is a recognized biochemical mechanism for drug resistance [164], which is schematized in Fig. (2). In this mechanism, the following events contribute to the development of resistance: decrease in drug accumulation either due to decreased influx or increased efflux; inactivation of the drug by cytoplasmic or nuclear molecules, such as GSH, MT, or proteins; export of Pt-GS conjugates by GS-X pump [131]; and binding of GSH to cisplatin-DNA monoadducts, preventing further crosslinks [165]. Although both GSH and MT can detoxify platinum drugs intracellularly or extracellularly by interacting the SH groups with the drugs and preventing them from binding to DNA [130, 166], GSH is the critical determinant in the tumor cell resistance to cisplatin and other alkylating agents [167].

There is considerable evidence linking GSH to cisplatin resistance [168]. Linear correlations between GSH levels and cisplatin resistance have been reported in human renal [169], bladder [170] and ovarian [13, 171] cancer cell lines and in human ovarian tumour biopsies [172]. The levels of GSH are determined by the synthetic enzyme -GCS and the salvage enzyme -glutamyl transpeptidase (-GT, GGT). High levels of GSH and GSH S-transferases (GSTs, GST ), the enzymes that catalyze the nucleophilic GSH reactivity [173], have been reported to play a role in the resistance of tumor cells to different anticancer drugs, including cisplatin [174-177]. As described in the last section, GSH reacts with cisplatin and other electrophilic compounds to form deactivated conjugates that are readily excreted by a GS-conjugated export pump. This reaction may occur spontaneously or with the help of the GSTs [178]. The GS-Pt-SG complexes (Pt : GSH = 1 : 2) have been found in tumor cells [179]. The removal of platinum is accompanied by the depletion of intracellular GSH. The GSH depletion sensitizes cells to many cytotoxic agents including cisplatin through activation of sphingomyelinase (SMase), which increases ceramide levels leading to SMase-induced apoptosis [180]. On the contrary, high intracellular concentrations of GSH (up to 10 mM) often correlate with cisplatin and carboplatin resistance, such as in the case of the cisplatin-resistant cell line A2780cisR, which possesses elevated levels of GSH [130]. For these reasons, the interaction of platinum drugs with GSH poses a severe obstacle for the design of new platinum-based drugs to overcome the cisplatin resistance [181]. On the other hand, increased levels of MTs have also been found in some cell lines with acquired resistance to cisplatin [20, 179]. Cisplatin binds to MT, with a stoichiometry of 10 Pt atoms per MT molecule and a binding rate constant significantly higher than that for GSH [182-184]. When cisplatin binds to MT, it loses NH3 ligands and displaces heavy-metal cations (e.g., Zn2+) from MT according to the 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 MT are resistant to some of these drugs in vitro [12, 185, 186]. It has been postulated that MT could scavenge chemotherapeutic compounds and nucleophilic radicals, protecting tumor cells from death [54, 187]. By protecting malignant cells, MT overexpression has been related to a worse prognosis for the patient [188, 189]. However, it is not yet clear whether MT plays a role in cisplatin resistance since MT overexpression only associates with cisplatin resistance in limited models [12, 190]. Recent studies report that transfection of the human MT-IIA cDNA into cells conferred over 4fold resistance to cisplatin [12], and up-to-date studies appear to show that cisplatin resistance can be prevented or reversed by the modulation of MT synthesis [191]. These findings indicate that the uncertain role of MT is being gradually refined. Thioredoxin (Trx) is a redoxactive sulfur-containing protein induced by various stresses and secreted from cells. It has been reported that cellular levels of Trx, thioredoxin reductase (TrxR), and glutaredoxin (Grx) are associated with cisplatin resistance, where increased cellular activity of the

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Trx system confers resistance to cisplatin [157]. The Trx and Grx systems can be inhibited by Pt-GS complexes, which is consistent with the correlation between increased Trx and cisplatin resistance [192]. Moreover, acting as a downstream effector of Smad7, Trx could suppress cisplatin-induced apoptosis in pancreatic cancer [193]. Reduced Trx is also an inhibitor of ASK1 [194], and the Trx related peroxiredoxin might protect cancer cells from apoptosis caused by cisplatin-induced oxidative stress [195]. EXO-SULFUR A. Toxicity of Platinum Anticancer Drugs Platinum anticancer drugs usually bring on severe general toxicity such as nephro- and neurotoxicity during chemotherapy, which may be related to their interactions with Met or Cys residues of proteins and peptides [1]. For example, cisplatin depletes protein-bound thiol (SH) groups in renal cells [196, 197] and inhibits various enzymes such as mitochondrial GSH reductase, Na+-K+-ATPase [198, 199], and respiratory enzymes [200]. Decreased GSH peroxidase activity concurrent with GSH depletion has been observed in rat kidneys following exposure to cisplatin [201-203]. Among the common toxicities induced by platinum anticancer drugs, nephrotoxicity is the major toxic effect encountered in the clinical application of cisplatin, which is mainly associated with the damage to the nondividing proximal tubule cells in the kidney [204]. To avoid or limit the nephrotoxicity in platinum chemotherapy, it is necessary to understand how cisplatin is metabolized to a nephrotoxin. In this process, the formation of Pt-GS complex and its transport out of the cell are the beginning steps [205]. The exported Pt-GS complex is cleaved to a platinum-cysteinylglycine complex by -glutamyl transpeptidase (GGT, a glycosylated membrane enzyme) on the cell surface [206, 207], which is further cleaved to a platinum-Cys complex by aminodipeptidase N on the cell surface. The platinum-Cys complex is taken into the cell and then converted to a highly reactive thiol by Cys-S-conjugate -lyase [208, 209]. Binding of the reactive thiol to essential proteins within the cell is toxic [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 Cytoprotective Agents Platinum-based chemotherapy leads to a variety of serious toxicities in clinical practice. However, the introduction of sulfur-containing molecules as cytoprotective agents could mitigate the severity of the toxic side effects of platinum drugs [1, 7, 19]. As a chemoprotectant, it should modulate the side effects in a beneficial way, but not affect the antitumor activity of the drug, and has no or only mild toxicity. Because of the preference of platinum for S-donor ligands, the majority of the potential chemoprotectants explored for platinum-based therapy thus far are sulfurcontaining compounds. The protective nature of these compounds is involved in prevention or reversal of Pt-S adducts in proteins. The potential reversibility of Pt-S bonds in the presence of other sulfur ligands suggests that certain Ptbound sulfur ligands can be substituted by other sulfur nucleophiles, and Pt can be transferred between various Scontaining molecules in vivo [117, 212, 213], which forms the chemical basis to alleviate the acute platinum toxicity using chemoprotectants. Thiocarbonyl and thiol donor compounds are promising chemoprotectants that have been evaluated in experimental and/or clinical studies. Among them, sodium thiosulphate (STS) [214], S-[N-(3-aminopropyl)-2-aminoethyl] dihydrogen thiophosphate (WR2721, amifostine) [215], diethyldithiocarbamate (DDTC) [216], disodium 2,2-dithiobisethane sulfonate (BNP7787, dimesna) [217], glutathione (GSH) and its esters [218] have attracted great attention. Other sulfur containing compounds such as thiourea, biotin, sulfathiazole, D-penicillamine, methimazole, tiopronin, 4-methylthiobenzoic acid (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 effective as a complete protective agent in human patients. Sulfur-containing amino acids such as L-Cys, L-Met, NAcCys, and DL-Hcy have been shown to reduce cisplatininduced toxicity and cisplatin uptake in different cells, thereO H3N Cl Pt H3N S CH2

H3N Pt H3N

Cl Cl HS CH2

O C CH NH C O O CH2 CH COOH NH2 NH CH2 COOH

C CH NH

NH

CH2

COOH

C O

CH2

CH NH2

COOH

GGT

H3N Pt H3N

Cl S CH2

C CH

NH

CH2

COOH Aminodipeptidase

H3N Pt H3N

Cl S CH2

COOH CH NH2

NH2 -lyase H3N Pt H3N S Cl

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

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fore have the potential for clinical application as chemoprotectants [221-223]. Currently, WR2721, GSH, and BNP7787 are representatives being applied or investigated in clinic as chemoprotectants, and hence they will be discussed in more detail in this review. WR-2721 WR-2721, together with STS and DDTC, belongs to the first generation platinum-protective agents and is also the most extensively evaluated cytoprotective agent. Thiol moieties in these agents are reactive with the nephrotoxic aquated species of cisplatin [17, 71]. WR-2721 is the only clinically approved chemoprotectant for cisplatin therapy [224-226]. Its administration before cisplatin reduces cisplatin-induced nephrotoxicity, myelosuppression and neurotoxicity without affecting the antitumor activity of the drug [227-229]. The protective effect of WR-2721 may depend on its tissue-specific accumulation and active cellular metabolism mediated by alkaline phosphatases [18]. As schematized in Fig. ( 8), WR-2721 is converted in vivo into the more reactive thiol form S-2-(3-aminopropylamino) ethanethiol (WR1065) by the catalysis of alkaline phosphatase [230], which is 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 cisplatininduced cytotoxicity in culture experiments [234]. Therefore, WR-2721 is a prodrug and its metabolite WR-1065 is the active form to protect the general toxicity by interacting with cisplatin in normal tissues. WR-1065 reacts with cisplatin similarly to GSH and forms Pt-thiolate adducts [71]. Plasma WR-2721 declines rapidly due to the dephosphorylation and the resulting WR-1065 has a short initial half-life due to its fast uptake by tissues and oxidation to disulfides, that eventually constitutes the major fraction in blood plasma and may serve as a pool for WR-1065 [16]. WR-1065 is capable of reversing monofunctional Pt-Met bonds, but this reversal is slow compared to that achieved with STS or DDTC. This low capacity has been taken as an explanation for the lack of nephroprotection when WR-2721 is given after platinum therapy [235]. WR-1065 is often administered to alleviate toxicities of platinum-based drugs and other alkylating agents such as cyclophosphamide [236, 237]. However, the reactivity of WR-2721 is not negligible and the alkaline phosphatase activity is not necessarily required if the concentrations of WR-2721 are sufficiently high. Kinetic data indicate that WR-2721 reacts with cisplatin and carboplatin with rate constants amounting to approximately 50% of those determined for WR-1065 [238]; and in vitro studies show that HPLC profiles of reaction products after incubation 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 comparatively fast (dephosphorylation time, 1.5 h) [239]. The ability of WR-2721 to reduce DNA platination is schedule-dependent in vitro , with pre-exposure or simultaneous exposure being more effective than post-exposure to WR-2721 [240]. However, protection from platinum-DNA adducts is unlikely to occur in blood cells at clinically achievable plasma concentrations of both cisplatin and WR2721, which has been manifested by the results of in vitro experiments in peripheral blood mononuclear cells [241] and findings in leukocytes from patients treated with cisplatin with or without prior administration of WR-2721 [242]. The Pt-DNA adduct level in cancer patients can be influenced by WR-2721, which further demonstrated its modulating ability on cisplatin toxicity [227]. Both myeloprotective and neuroprotective properties of WR-2721 have been substantiated or suggested by in vitro studies in hematopoietic progenitor cells [243, 244] or by neurite outgrowth assay [245] in the presence of carboplatin, respectively. WR-2721 accumulates more rapidly and effectively in liver, lung, kidney, bone marrow, intestinal mucosa and skin than in tumors after administration to tumor-bearing mice and rats [246]. Various preclinical models have demonstrated the partial protection from cisplatin-induced neprotoxicity [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 with or without WR-2721; and partial protection from nephrotoxicity induced by a high-dose chemotherapy regimen comprising carboplatin plus ifosfamide plus etoposide has also been reported. [256] The effects of WR-2721 depend on the timing of administration. In mice, to reduce the renal injury and lethality, WR-2721 must be given shortly before cisplatin, indicating WR-2721 prevents rather than reverse cellular damage [247]. The phase I clinical studies show that WR-2721 premedication permits a slight increase in both cisplatin [257] and carboplatin doses [258] as compared to their standard amounts. Higher therapeutic benefit has been demonstrated in melanoma patients treated with elevated cisplatin doses under WR-2721 protection, which produce only transient nephrotoxicity in a limited number of patients [259]. WR-2721 has only a minor influence on the pharmacokinetics of cisplatin [260], however, in the case of carboplatin, higher platinum concentrations in plasma and tissues and enchanced antitumour activity in mice were observed [250, 261]. Therefore, the pharmacokinetic influence of WR-2721 is dependent on the nature of the drugs themselves.

OH H2N (H2C)3 H N (H2C)2 S P OH WR-2721 WR-1065 O alkaline phosphatase H2N (H2C)3 H N (H2C)2 SH

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

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WR-2721 may be considered as a chemoprotectant for the reduction of nephrotoxicity, but there are some reservations regarding its routine use for the prevention of neurotoxicity or otoxicity due to insufficiency of available data. Furthermore, WR-2721 may cause an increase in nausea and vomiting as well as transient hypotension in some patients. Only after these problems get resolved can a broader use of WR-2721 in clinic becomes possible. GSH Glutathione (GSH) is a ubiquitous intracellular sulfurcontaining tripeptide that displays a variety of cellular functions (vide supra). As a detoxifying agent, GSH protects DNA by scavenging intracellular cisplatin [262] and compromises the efficacy of the drug; as a cytoprotective agent, however, GSH alleviates drug induced toxicity and possesses a great advantage of lacking major toxicity. For this reason, exogenous GSH could be introduced into the body to realize the protective intention. The protective effect of GSH seems to depend on its tissue-specific accumulation and its active cellular metabolism, mediated by -GT [263]. Extracellular GSH degrades with the aid of -GT; the degradation product cysteinylglycine shows higher reactivity than GSH towards cisplatin and inactivates the drug more rapidly, which may play a key role in the protective mechanism [264]. Currently, GSH is the most extensively explored experimental cytoprotectant against cisplatin toxicity [265, 266]. It is well documented that the renal toxicity [267] and the neurotoxic effects [96, 268-270] induced by cisplatin can be alleviated or even prevented by GSH. The cisplatin dose could be escalated to 175% of the standard amount when the drug was administered with GSH in a phase I trial [271]. Several studies in animals demonstrate that GSH administered prior to or after cisplatin can decrease the acute lethal toxicity, and the protective concentrations of GSH appear not to affect the antitumor effects of cisplatin [272-274]. In addition, GSH can also provide chemoprotection from carboplatin ototoxicity [275] and oxaliplatin neurotoxicity [276]. Moreover, the esters of GSH can also ameliorate cisplatininduced nephro- and neurotoxicity in different animal models [205]. BNP7787 BNP7787 (2) is the only second generation cytoprotectant coming to an advanced clinical stage, and is currently under clinical investigation to protect or mitigate toxicities associated with platinum-based chemotherapy, such as nephrotoxicity and neurotoxicity [17, 217]. Another cytoprotectant closely related to BNP7787 is 2-mercaptoethane sulfonate (mesna, 3), a commonly used nephroprotectant in ifosfamide therapy [277]. The efficacy of mesna in preventing cisplatin-induced nephrotoxicity is still under preclinical evaluations [278] though it could not be proved in early preclinical studies [279, 280]. BNP7787 is the dimer of mesna,

but their biochemical and biomedical properties are different from each other. Mesna distributes mainly in the extracellular compartment, which differs markedly from WR1065 that distributes equally between the extra- and intracellular compartments [262, 236]. The reaction of mesna with cisplatin is similar to the cytoprotective mechanism of GSH, also involving the formation of Pt-thiolate adducts [281]. In contrast to mesna, BNP7787 is inert and relatively stable in blood plasma. It does not interfere with the in vitro and in vivo antitumor activity of cisplatin and carboplatin [277]. This may be due to the slow reactivity and short in vivo residence time of BNP7787 ( ca 2 h), together with the much lower concentration of mesna in the circulation. The nephro- and neuroprotective effects produced by BNP7787 given to rats shortly before cisplatin and carboplatin enable the maximal increases in tolerable doses of both drugs [17]. BNP7787 is cleared rapidly from the blood via the kidneys, where it is reduced to the pharmacologically active thiol form mesna within the tubular epithelium by a mechanism involving cytosolic GSH reductase [282, 283]. BNP7787 reacts more rapidly with the monoaquated species of cisplatin than the unhydrolyzed drugs, and the nephroprotective properties are attributed to specific neutralization of the aquated species of cisplatin in the renal tubules [284]. Phase I clinical and pharmacokinetic studies show that BNP7787 produces little toxicity and does not influence the pharmacokinetics of cisplatin [285]. BNP7787 is currently in phase III trials in the USA and Europe for the prevention of cisplatin-induced neurotoxicity [217]. Others Diethyldithiocarbamic acid (DDTC, 4) has been shown to reduce cisplatin-induced nephrotoxicity in several animal studies and in patients when administered after the drug [286]. DDTC could remove platinum-bound biological nucleophiles, resulting in the formation of Pt(DDTC)2, and restore, at least in part, several enzyme activities inhibited by cisplatin. This restoration may be resulted from platinum removal from Met or Cys residues [287]. However, the use of DDTC in the clinic has been impeded by severe sympathetic dysautonomia (flushing, diaphoresis and tachycardia) [281]. The sodium salt of DDTC, sodium diethyldithiocarbamate (NaDDTC), and its dimer, bis(N,N-diethylthiocarbamoyl)disulfide (disulfiram), have been extensively studied as cytoprotectants; but randomized trials did not give positive support to the promising results from preclinical and early clinical studies [288, 289].

S N HS 4

C2H5 C2H5 S S 5

O (CH2)4 C OH

O-Na+ O S O 2 CH2CH2 S S CH2CH2

O-Na+ S O O -S H2 CH2C Na + 3

OS O O

-Lipoic acid (thioctic acid, 5) is an essential cofactor for mitochondrial enzymes that has been probed as a biological antioxidant and a potent free-radical scavenger [290]. The ability of -lipoic acid to bind metal and regenerate GSH

The Role of Sulfur in Platinum Anticancer Chemotherapy

Anti-Cancer Agents in Medicinal Chemistry, 2007, Vol. 7, No. 1 29

makes it possible as a chemoprotectant for platinum therapy and the suitability is currently under clinical evaluation [291]. Beneficial effects were observed in a few patients who had developed a neuropathy following combination therapy with oxaliplatin plus raltitrexed [292]. Otoprotective [291, 293] and nephroprotective effects in rats [294], both associated with a restoration of antioxidant enzyme activities, have been reported. Sodium thiosulfate (STS, Na2S2O3) can be cleared rapidly from the circulation via kidneys [295], therefore it has been explored for protective properties to reduce the nephrotoxicity of cisplatin [296]. In addition, STS has been shown to protect against carboplatin ototoxicity in both animal and human studies [275]. However, inactivation of cisplatin by STS was observed in preclinical studies when both agents were administered to the same compartment [297, 298]. Although the inactivation could be offset by a more tolerable cisplatin dose resulting from nephroprotective effects, cumulative neurotoxicity prohibits application of such a high-dose regimen [299]. For this reason, STS has mainly been studied as an intravenous cytoprotectant to neutralize systemic platinum cooperatively with intracavitary high-dose cisplatin [300]; but this treatment modality has remained experimental, since intracavitary administration of cisplatin has not become a routine practice. D-Methionine (D-Met) is one of the most effective sulfur-containing compounds for protecting against cisplatin nephrotoxicity without interfering with its antitumor activity [301]. D-Met behaves differently from other chemoprotectants in that it is ineffective against melphalan toxicity but very effective against cisplatin [302]. D-Met can protect hair cells from cisplatin damage in rats or inner hair cells from carboplatin damage in chinchillas [303]. As one of the most easily oxidizable amino acids, D-Met may act as a free radical scavenger to protect cochlear tissue and hence provides chemoprotection from carboplatin ototoxicity [275]. Finally, the antithyroid drug methimazole has a free SH group that could potentially protect against cisplatin-induced acute nephrotoxicity in vivo [304]. CONCLUDING REMARKS This review presents an overview about the impact of sulfur on the platinum anticancer chemotherapy. Based on the experimental facts found over the years, it can be concluded that sulfur is a double-edged sword in the platinum chemotherapy: it compromises the efficacy of platinumbased drugs on one side, it provides protection against toxicity induced by platinum-based drugs on the other side. The platinum-sulfur interactions exist in almost every process of platinum chemotherapy, but there are still a number of ambiguities concerning the mechanism of action and the implication of the interactions. Therefore, continuing research in this area is highly expected in the coming years. New findings on these aspects would be helpful for effective use of the existing platinum drugs and be beneficial to the design of new platinum-based drugs. For example, recent studies have revealed that the transport, uptake, subcellular distribution and export of a substantial fraction of platinum drugs are influenced by transporters and metallochaperones that normally manage Cu homeostasis, especially the Met-rich uptake

transporter CTR1 [123, 305]. However, it is not clear whether platinum drugs are actually transported into/out of cells by the Cu transporters or the effect is merely a secondary one. In addition, whether any of the platinum drugs is actually the substrate for these transporters and whether sulfur plays a role in this process are still open questions. Researches on such fields are full of challenges, but the great value behind them deserves the endeavor. ACKNOWLEDGEMENT We are grateful for the financial supports from the National Science Foundation of China (No.s 20231010, 20228102 and 30370351), China Postdoctoral Science Foundation (No. 2003034374) and the Natural Science Foundation of Jiangsu Province (No. BK 2005209). ABBREVIATIONS ASK1 BNP7787 BSO CBDCA Cys DACH DTTC ESMS -GCS Grx GSH GSSG 5-GMP HAS Hcy His HMG Mesna Met MT N-AcCys STS Trx TrxR WR-2721 WR-1065 = Apoptosis signal-regulating kinase 1 = Disodium 2,2-dithiobisethane sulfonate; dimesna = Buthionine sulphoximine = Cyclobutanedicarboxylate = Cysteine = 1,2-Diaminocyclohexane = Diethyldithiocarbamate = Electrospray mass spectrometry = -Glutamyl cysteine synthetase = Glutaredoxin = L--Glutamyl-L-cysteinyl-glycine; (reduced) glutathione = Glutathione disulfide = 5-Guanosine monophosphate = Human serum albumin = Homocysteine = Histidine = High-mobility group = 2-Mercaptoethanesulfonate = Methionine = Metallothionein = N-acetylcysteine = Sodium thiosulofate = Thioredoxin = Thioredoxin reductase = S-[N-(3-amiopropyl)-2-aminoethyl] dihydrogen thiophosphate; amifostine = S-2-(3-aminopropylamino)ethanethiol

GGT, -GT = -Glutamyl transpeptidase

GST, GST = Glutathione S-transferase ()

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Received: November 4, 2005

Revised: February 7, 2006

Accepted: April 10, 2006