Surface and Electrostatic Contributions to DNA-Promoted Reactions of Platinum(II) Complexes with Short Oligonucleotides: A Kinetic Study

Elmroth, Sofi K. C.; Lippard, Stephen J.

doi:10.1021/ic00125a024

Cited by 48 publications

(69 citation statements)

References 2 publications

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“…This observation may result from nucleophilic groups in the G-25 packing material displacing the radiocarbonlabeled cyclobutanedicarboxylate from the Pt-DNA monoadducts. Alternatively, the ethanol precipitation may have carried out of solution a preassociation complex of aquated carboplatin electrostatically bound to the DNA (19). This possibility was minimized by quenching the platination reaction with NaCl prior to precipitation in order to electrostatically shield the polyphosphate DNA backbone from any positively charged aquated compound.…”

Section: Resultsmentioning

confidence: 99%

Kinetics of Carboplatin−DNA Binding in Genomic DNA and Bladder Cancer Cells As Determined by Accelerator Mass Spectrometry

Hah

Stivers

White

et al. 2006

Chem. Res. Toxicol.

100

101

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Cisplatin and carboplatin are platinum-based drugs that are widely used in cancer chemotherapy. The cytotoxicity of these drugs is mediated by platinum-DNA monoadducts and intra-and interstrand diadducts, which are formed following uptake of the drug into the nucleus of cells. The pharmacodynamics of carboplatin display fewer side effects than for cisplatin, albeit with less potency, which may be due to differences in rates of DNA adduct formation. We report the use of accelerator mass spectrometry (AMS), a sensitive detection method often used for radiocarbon quantitation, to measure both the kinetics of [ 14 C]carboplatin-DNA adduct formation with genomic DNA and drug uptake and DNA binding in T24 human bladder cancer cells. Only carboplatin-DNA monoadducts contain radiocarbon in the platinated DNA, which allowed for calculation of kinetic rates and concentrations within the system. The percent of radiocarbon bound to salmon sperm DNA in the form of monoadducts was measured by AMS over 24 h. Knowledge of both the starting concentration of the parent carboplatin and the concentration of radiocarbon in the DNA at a variety of time points allowed calculation of the rates of Pt-DNA monoadduct formation and conversion to toxic cross-links. Importantly, the rate of carboplatin-DNA monoadduct formation was approximately 100-fold slower than that reported for the more potent cisplatin analogue, which may explain the lower toxicity of carboplatin. T24 human bladder cancer cells were incubated with a subpharmacological dose of [ 14 C]carboplatin, and the rate of accumulation of radiocarbon in the cells and nuclear DNA was measured by AMS. The lowest concentration of radiocarbon measured was approximately 1 amol/10 µg of DNA. This sensitivity may allow the method to be used for clinical applications.

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Section: Resultsmentioning

confidence: 99%

Kinetics of Carboplatin−DNA Binding in Genomic DNA and Bladder Cancer Cells As Determined by Accelerator Mass Spectrometry

Hah

Stivers

White

et al. 2006

Chem. Res. Toxicol.

100

101

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“…Reactions of 2 in acidic conditions are complicated by the hydrolysis of 2 to 3 (Scheme 2) and this occurs in parallel with the direct reaction of 2 with the oligonucleotide. Since 3 is considerably more reactive towards nucleobases than 2, [22,23] the commonly used approximation neglecting the reaction between 3 and the oligonucleotide [12,13,16,24] yields unprecise results. Our solution to the problem resided in separate investigations of the reaction of 3 in a series of experiments that we reported earlier [18] (indicated by bold arrows in Schemes 2 and 3) and allowed the reactions of 2 (Scheme 2) and 4 (Scheme 3) to be studied with a reduced number of variables.…”

Section: IImentioning

confidence: 99%

A Complete Kinetic Study of GG versus AG Platination Suggests That the Doubly Aquated Derivatives of Cisplatin Are the Actual DNA Binding Species

et al. 2000

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The hairpin-stabilized double-stranded oligonucleotides d(TATGGTATT4ATACCATA) (I) and d(TATAGTATT4ATACTATA) (II) were allowed to react with the three aquated forms of the antitumor drug cisplatin (cis-[PtCl2(NH3)2], 1) which are likely candidates for DNA binding, that is, cis-[PtC1(NH3)2(H2O)]+ (2), cis-[Pt(NH3)2(H2O)2]2+ (3), and its conjugate base cis-[Pt(OH)(NH3)2(H2O)]+ (4). The reaction between I and [Pt(NH3)3(H2O)]2+ (5) was also studied for comparison. All reactions were monitored by HPLC. The platination reactions of I and II were carried out in NaClO4 (0.1M) at 293 K and at a constant pH of 4.5 +/- 0.1 for 2, 3, and 5. The data relative to the platination by 4 were obtained from measurements in unbuffered NaClO4 solutions (0.1M) at a starting pH close to neutrality, where 3 and 4 are present in equilibrium. In this case, a fit function describing the pH-time curve allowed the determination of the actual concentrations of 3, 4, and the dihydroxo complex. The platination rate constants characterizing the bimolecular reactions between either I or II and 2, 3, and 4 were individually determined along with the rate constants for hydrolysis of the chloro-monoadducts and for the chelation reactions of the aqua-monoadducts. The reactivity of compounds 2-5, which have the general formula cis-[Pt(NH3)2(H2O)(Y)]2+/-, decreases in the order 3>4>5>>2, that is, Y= H2O > OH- >NH3 >> Cl-, which is the order of decreasing hydrogen-bond donating ability of Y. Deprotonation of 3 to 4 reduces the reactivity of the platinum complex only by a factor of approximately equals 2, and both complexes discriminate between the different purines of I and II in the same manner. Whereas 3 and 4 react approximately three times faster with the GG sequence of I than with the AG sequence of II, 2 shows a similar reactivity towards both sequences. In view of the well-established preferential binding of cisplatin to GG sequences of DNA in vivo and in vitro, this result suggests that the actual DNA platination species are derived from double hydrolysis of cisplatin.

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“…The association between oligonucleotides and platinum complexes result mainly from electrostatic interactions and hydrogen bonds (14,15). Therefore, these interactions existing in solution will be maintained in the gas phase and ESMS spectra will reflect the distribution of the various species in solution, since they have strong gas phase stabilities.…”

Section: (H 2 O) 2 ]mentioning

confidence: 99%

“…It is supposed that prior to the binding of cisplatin to one or two guanines (10 -13), the aforementioned cationic complexes associate with polyanionic DNA through electrostatic interactions. Lippard and co-worker (14,15) have shown that the rate of platination increases with the length of single-stranded oligonucleotides from 8-to 16-mer, whereas single-stranded and duplex oligonucleotides of the same length displayed identical reactivity. According to these results, the authors proposed a two-step mechanism for DNA platination.…”

mentioning

confidence: 99%

Determination by Electrospray Mass Spectrometry of the Outersphere Association Constants of DNA/Platinum Complexes Using 20-mer Oligonucleotides and ([Pt(NH3)4]2+, 2Cl−) or ([Pt(py)4]2+, 2Cl−)

Carte

Legendre²,

Leize³

et al. 2000

Analytical Biochemistry

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Surface and Electrostatic Contributions to DNA-Promoted Reactions of Platinum(II) Complexes with Short Oligonucleotides: A Kinetic Study

Cited by 48 publications

References 2 publications

Kinetics of Carboplatin−DNA Binding in Genomic DNA and Bladder Cancer Cells As Determined by Accelerator Mass Spectrometry

Kinetics of Carboplatin−DNA Binding in Genomic DNA and Bladder Cancer Cells As Determined by Accelerator Mass Spectrometry

A Complete Kinetic Study of GG versus AG Platination Suggests That the Doubly Aquated Derivatives of Cisplatin Are the Actual DNA Binding Species

Determination by Electrospray Mass Spectrometry of the Outersphere Association Constants of DNA/Platinum Complexes Using 20-mer Oligonucleotides and ([Pt(NH3)4]2+, 2Cl−) or ([Pt(py)4]2+, 2Cl−)

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