Sensitive species-specific monitoring of a new triplatinum anti-cancer drug and its potential related compounds in spiked human plasma by cation-exchange HPLC-ICP-MS

Vacchina, Véronique; Torti, L.; Allievi, Cecilia; Łobiński, Ryszard

doi:10.1039/b302241b

Cited by 38 publications

(30 citation statements)

References 19 publications

(37 reference statements)

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“…[8][9][10] One potential problem for this class of complexes is, however, their low stability against sulfur-containing biomolecules such as reduced glutathione (GSH). [11][12][13] In the search for more stable polynuclear Pt II complexes, we have designed several di-and trinuclear complexes in which the Pt II centers are bridged by bulky aromatic linkers. [14][15][16] These complexes showed interesting cytotoxicity against human and mouse cell lines.…”

Section: Introductionmentioning

confidence: 99%

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

Zhu¹,

Zhao²,

Zhu³

et al. 2009

Chemistry A European J

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The DNA binding and cross-linking modes of a trinuclear platinum complex [Pt(3)Cl(3)(hptab)][ClO(4)](3) (1; hptab = N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene) and its dinuclear analogue [Pt(2)Cl(2)(m-tpxa)]Cl(2) (2; m-tpxa = N,N,N',N'-tetra(2-pyridylmethyl)-m-xylylene diamine) are reported and compared. The adducts of 1 and 2 with 18-mer duplex N1, 5'-d(GAAGAAGTCACAAAATGT)-3'5'-d(ACATTTTGTGACTTCTTC)-3', have been characterized by means of denaturing polyacrylamide gels, Maxam-Gilbert sequencing, and MALDI-TOF mass spectrometry combined with enzymatic degradation to obtain insights into structural features responsible for the differences in their antitumor activities. The cytotoxic-active complex 1 readily forms various DNA adducts, such as through 1,3- and 1,4-intrastrand cross-links, and in particular, the unique and unprecedented interstrand cross-linked triadducts. In contrast, the cytotoxic-inactive complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intra- and -interstrand cross-links. Digestion of the DNA adducts of 1 shows that the cleavage is completely blocked at one nucleotide before the cross-linked guanine residues on the opposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated guanine site and stops at one nucleotide prior to the second platinated site, confirming that very few 1,3-intrastrand cross-links are formed by 2. These results are supported by molecular-modeling studies of intra- and interstrand cross-links of duplex N1 with 1 and 2. The remarkable differences between 1 and 2 in DNA binding and cross-linking provide mechanistic insights into their different cytotoxicity against the tumor cell lines; these insights are useful for designing future antitumor agents.

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Section: Introductionmentioning

confidence: 99%

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

Zhu¹,

Zhao²,

Zhu³

et al. 2009

Chemistry A European J

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“…Interaction of Pt-containing drugs with target biomolecules li ke metallothioneins (MTs) ( 13,14), or sulfur-containing biocompounds (15,16) has been reported. The determination of free cisplatin in spiked human serum (17) or the separation of some Pt-species in spiked human plasma (18), are examples of Pt metallomic studies. However, to our knowledge very few in vivo studies concerning Pt biomolecules speciation have been reported (19).…”

Section: Introductionmentioning

confidence: 99%

Accumulation, Fractionation, and Analysis of Platinum in Toxicologically Affected Tissues after Cisplatin, Oxaliplatin, and Carboplatin Administration

Esteban-Fernández

Verdaguer

Ramírez‐Camacho

et al. 2008

Journal of Analytical Toxicology

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IAntitumoral Pt-containing drugs present side effects like nephrotoxicity and ototoxicity. Several systematic experiments have been carried out with Wistar rats treated with cisplatin, carboplatin, and oxaliplatin to study Pt-drugs accumulation and elimination, and Pt-biomolecule distribution in the cells and cytosols of ear, kidney, and liver. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis shows a cisplatin accumulation capability between oxaliplatin (the highest) and carboplatin (the lowest). The maximum concentration of Pt in all the organs studied was achieved around the first week after cisplatin treatment. During the first 30 days, the elimination was very fast, decreasing in the subsequent 60 days in all the organs. Analysis of cytosols by liquid chromatography (LC)-ICP-MS showed an analogous behavior. In most samples, the distribution of the three drugs in the cellular and cytosolic fractions was similar for all the tissues. For kidney and ear, approximately 60% and 30%, respectively, of the metal accumulated was present in the cytosol, the cytosolic fractions smaller than 50 KDa being especially important. Cisplatin-biomolecule interaction strength under denaturing conditions was evaluated by LC-ICP-MS and showed a quite strong bond.

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“…Indeed, the products of BBR3464 blood metabolism may be mimicked by GSH reactions. [31] In contrast, the 1,1/c,c dinuclear structure initially remains intact upon reaction with GSH and methionine. The reactions are slower than those with the 1,1/t,t isomer, but eventually the NH 3 group trans to the sulfur atom is lost.…”

Section: Introductionmentioning

confidence: 99%

Effects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long‐Range DNA Interstrand Cross‐Links by Dinuclear Platinum Antitumor Complexes

Zhang¹,

Thomas²,

Berners‐Price³

et al. 2008

Chemistry A European J

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Reported herein is a detailed study of the kinetics and mechanism of formation of a 1,4-GG interstrand cross-link by the dinuclear platinum anticancer compound [ 15 N][{cis-PtCl-(NH 3 ) 2 } 2 {μ-NH 2 (CH 2 ) 6 NH 2 }] 2+ (1,1/c,c (1)). The reaction of [ 15 N]1 with 5′-{d(ATATGTACATAT) 2 } (I) has been studied by [ 1 H, 15 N] HSQC NMR spectroscopy in the presence of different concentrations of phosphate. In contrast with the geometric trans isomer (1,1/t,t), there was no evidence for an electrostatic preassociation of 1,1/c,c with the polyanionic DNA surface, and the pseudo-first-order rate constant for the aquation of [ 15 N]1 was actually slightly higher (rather than lower) than that in the absence of DNA. When phosphate is absent, the overall rate of formation of the cross-link is quite similar for the two geometric isomers, occurring slightly faster for 1,1/t,t. A major difference in the DNA binding pathways is the observation of phosphate-bound intermediates only in the case of 1,1/c,c. 15 mM phosphate causes a dramatic slowing in the overall rate of formation of DNA interstrand cross-links due to both the slow formation and slow closure of the phosphate-bound monofunctional adduct. A comparison of the molecular models of the bifunctional adducts of the two isomers shows that helical distortion is minimal and globally the structures of the 1,4 interstrand cross-links are quite similar. The effect of carrier ligand was investigated by similar studies of the ethylenediamine derivative [ 15 N]1-en. A pK a value of 5.43 was determined for the [ 15 N]1,1/c,c-en diaquated species. The rate of reaction of [ 15 N]1-en with duplex I is similar to that of 1,1/c,c and the overall conformation of the final adduct appears to be similar. The significance of these results to the development of "second-generation" polynuclear platinum clinical candidates based on the 1,1/ c,c chelate (dach) series is discussed.

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Sensitive species-specific monitoring of a new triplatinum anti-cancer drug and its potential related compounds in spiked human plasma by cation-exchange HPLC-ICP-MS

Cited by 38 publications

References 19 publications

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

Accumulation, Fractionation, and Analysis of Platinum in Toxicologically Affected Tissues after Cisplatin, Oxaliplatin, and Carboplatin Administration

Effects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long‐Range DNA Interstrand Cross‐Links by Dinuclear Platinum Antitumor Complexes

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