The Chemistry of Cisplatin in Aqueous Solution

Berners‐Price, Susan J.; Appleton, T. G.

doi:10.1385/1-59259-012-8:3

Cited by 63 publications

(73 citation statements)

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“…Hydrolytic activation of cisplatin is to some extent suppressed by high chloride concentrations in extracellular fluids, but is assumed to be promoted by the low chloride concentrations present inside the cell. However, it should be kept in mind that these assumptions are based on equilibria constants, while chemical equilibrium is not attained in biological systems (for a review see Berners-Price and Appleton 2000). Cisplatin reacts with a variety of nitrogen-and sulphur-containing biomolecules by ligand exchange reactions.…”

Section: The First Generation -Cisplatinmentioning

confidence: 99%

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

381

349

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Thirty years after the onset of the first clinical studies with cisplatin, the development of antineoplastic platinum drugs continues to be a productive field of research. This article reviews the current preclinical and clinical status, including a discussion of the molecular basis for the activity of the parent drug cisplatin and platinum drugs of the second and third generation, in particular their interaction with DNA. Further emphasis is laid on the development of third generation platinum drugs with activity in cisplatin-resistant tumours, particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the promising and more recently evolving field of non-classic ( trans- and multinuclear) platinum complexes. The development of oral platinum drugs and drug targeting strategies using liposomes, polymers or low-molecular-weight carriers in order to improve the therapeutic index of platinum chemotherapy are also covered.

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Section: The First Generation -Cisplatinmentioning

confidence: 99%

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

381

349

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“…The initial photolysis in water produces the corresponding complex, [Ru(bpy) 2 2+ , with quantum yields, Φ, of 0.018 (λ irr = 400 nm) and 0.16 (λ irr ≥ 400 nm), respectively, followed by the formation of cis- [Ru(bpy) 2 (H 2 O) 2 ] 2+ with continued irradiation [11,12]. The cation cis- [Ru(bpy) 2 2 ] 2+ , known to covalently bind to nuclear DNA and disrupt cellular processes, including transcription and translation [15][16][17][18][19]. Similarly, the formation of cis- [ 6 ] 2+ is observed in water upon irradiation with visible light (Φ = 0.09, λ irr = 509 nm); the product binds covalently to ds-DNA, and a 34-fold increase in toxicity is observed with photolysis [20].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity

Palmer

Peña

Sears

et al. 2013

Phil. Trans. R. Soc. A.

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The cyclometallated Ru(II) complexes cis -[Ru(phpy)(phen)(CH 3 CN) 2 ](PF 6 ) ( 1 ; phpy − =deprotonated 2-phenylpyridine, phen=1,10-phenanthroline) and cis -[Ru(phpy)(bpy)(CH 3 CN) 2 ](PF 6 ) ( 2 ; bpy=2,2′-bipyridine) were investigated as potential agents for photodynamic therapy. The presence of phpy − in the coordination sphere results in a red-shift of the Ru→phen and Ru→bpy metal-to-ligand charge transfer of 1 and 2 , respectively, thus improving the tissue penetration of light while maintaining the efficient photo-induced ligand exchange required for DNA binding. The 14-fold enhancement of OVCAR-5 cell death that occurs upon irradiation with 690 nm light can be attributed to photo-aquation. The role of glutathione (GSH) on the toxicity of the complex was also explored. Complexes 1 and 2 undergo ligand substitution in the presence of GSH in the dark, such that the metal may covalently bind to biomolecules. The combination of photo-induced ligand exchange and GSH-facilitated ligand exchange may explain the observed cytotoxicity.

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“…4 The DNA-reactive platinum species are considered to be monoaquo and diaquo complexes—in general [Pt(amine) 2 (H 2 O) 2 ] 2+ or [Pt(amine) 2 -(Cl)(H 2 O)] + —produced upon hydrolysis of the administered drugs, and the chemistry of these species has been well examined. 5 While this concept has been useful in rationalizing some structure–activity relationships, there is increasing understanding that even anions with nominally weak affinity for platinum—CO 3 2−;6,7 SO 4 2−;8 PO 4 3− and even RCOO −9 —become physiologically relevant ligands because of their high concentrations in plasma and cells. Similarly, cellular accumulation of platinum drugs is multifactorial with evidence for both passive and active transporter-mediated processes.…”

Section: Introductionmentioning

confidence: 99%

Effects of Noncovalent Platinum Drug–Protein Interactions on Drug Efficacy: Use of Fluorescent Conjugates as Probes for Drug Metabolism

et al. 2011

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The overall efficacy of platinum based drugs is limited by metabolic deactivation through covalent drug–protein binding. In this study the factors affecting cytotoxicity in the presence of glutathione, human serum albumin (HSA) and whole serum binding with cisplatin, BBR3464, and TriplatinNC, a “noncovalent” derivative of BBR3464, were investigated. Upon treatment with buthionine sulfoximine (BSO), to reduce cellular glutathione levels, cisplatin and BBR3464-induced apoptosis was augmented whereas TriplatinNC-induced cytotoxicity was unaltered. Treatment of A2780 ovarian carcinoma cells with HSA-bound cisplatin (cisplatin/HSA) and cisplatin preincubated with whole serum showed dramatic decreases in cytotoxicity, cellular accumulation, and DNA adduct formation compared to treatment with cisplatin alone. Similar effects are seen with BBR3464. In contrast, TriplatinNC, the HSAbound derivative (TriplatinNC/HSA), and TriplatinNC pretreated with whole serum retained identical cytotoxic profiles and equal levels of cellular accumulation at all time points. Confocal microscopy of both TriplatinNC-NBD, a fluorescent derivative of TriplatinNC, and TriplatinNC-NBD/HSA showed nuclear/nucleolar localization patterns, distinctly different from the lysosomal localization pattern seen with HSA. Cisplatin-NBD, a fluorescent derivative of cisplatin, was shown to accumulate in the nucleus and throughout the cytoplasmwhile the localization of cisplatin-NBD/HSA was limited to lysosomal regions of the cytoplasm. The results suggest that TriplatinNCcan avoid high levels of metabolic deactivation currently seen with clinical platinum chemotherapeutics, and therefore retain a unique cytotoxic profile after cellular administration.

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The Chemistry of Cisplatin in Aqueous Solution

Cited by 63 publications

References 0 publications

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity

Effects of Noncovalent Platinum Drug–Protein Interactions on Drug Efficacy: Use of Fluorescent Conjugates as Probes for Drug Metabolism

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