A Single Slow Electron Triggers the Loss of Both Chlorine Atoms from the Anticancer Drug Cisplatin: Implications for Chemoradiation Therapy

Kopyra, Janina; Koenig-Lehmann, Constanze; Bald, Ilko; Illenberger, Eugen

doi:10.1002/ange.200903874

Cited by 11 publications

(6 citation statements)

References 17 publications

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“…Presumably, the liberated cisPt then reacts with water in an exothermic process. 34 The green curves, where both • OH radicals and hydrated electrons are captured, are similar to the control spectra at 0 Gy (black curves), as expected, but also bear some slight resemblance to the hydrated electron curve, presumably because of the small amount of nonscavenged hydrated electrons. We observe residual breakage of the cisPt bond, corresponding to about 0.13% for one bond broken and 1.4% for two bonds broken.…”

Section: Denaturing Gel Electrophoresissupporting

confidence: 74%

“…A priori, this double bond break in ODN-GTG-cisPt can occur in two ways: either a cisPt-guanine bond is first broken and the remaining fragments react with and dissociate the other cisPt-guanine bond, or the transient anion formed via DET dissociates by simultaneously breaking the two cisPt-guanine bonds. The latter mechanism has been observed by Kopyra et al 34 using a mass spectrometer as a detector, in LEE impact experiments on gaseous cisPt, containing its original chlorine atoms. They found that a transient anion formed at ~0 eV dissociates by simultaneously breaking the bonds between Pt and the chlorine atoms.…”

Section: Discussionmentioning

confidence: 69%

“…From ab initio calculations, those orbitals have a repulsive σ* character along all cisPt coordination axes. 34 This results in possible channels for one or two cisPt-guanine bond cleavage, if the time of electron occupation in that state is sufficiently long (i.e., of the order of a vibrational period of a cisPt-guanine bond). 35 From the rotovibrational ground state, the anion needs a minimum energy to dissociate called the thermodynamic threshold (ΔH) given by the bond dissociation energy, D(A-B), minus the electron affinity (EA) of the fragment on which the electron stabilizes 35 (1) Thus, for DET to occur, the potential energy surfaces of the transient anion along the cisPtguanine bonds must at least partly lie above ΔH in the Franck-Condon region.…”

Section: Discussionmentioning

confidence: 99%

“…33 This technique has also been used to show the interaction of LEEs with cisPt, which leads to the loss of chlorine from cisPt in a one-and two-step process via dissociative electron attachment. 34 In the present work, the damages induced by hydrated electrons, generated by water radiolysis, on olignucleotide-cisPt complexes are investigated for cisPt mono-and diadducts.…”

Section: Introductionmentioning

confidence: 99%

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Hydrated Electrons React with High Specificity with Cisplatin Bound to Single-Stranded DNA

et al. 2013

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Short oligonucleotides TTTTTGTGTTT and TTTTTTTGTTT in solution with and without cisplatin (cisPt) bound to the guanine bases were irradiated with γ-rays at doses varying from 0 to 2500 Gy. To determine the effect of hydrated electrons from water radiolysis on the oligonucleotides, we quenched (•)OH radicals with ethylenediaminetetraacetic acid (EDTA) and displaced oxygen, which reacts with hydrated electrons, by bubbling the solution with wet nitrogen. DNA strand breaks and platinum detachment were quantified by gel electrophoresis. Our results demonstrate that hydrated electrons react almost exclusively at the position of the cisPt adduct, where they induce cisPt detachment from one or both guanines in the oligonucleotide. Given the high yield of hydrated electrons in irradiated tissues, this reaction may be an important step in the mechanism of radiosensitization of DNA by cisPt.

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Section: Denaturing Gel Electrophoresissupporting

confidence: 74%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hydrated Electrons React with High Specificity with Cisplatin Bound to Single-Stranded DNA

et al. 2013

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“…This DET mechanism has uncovered the long-existing mystery of why CDDP results in a preferential binding to two neighboring G bases in DNA 21 . Subsequently, this DET mechanism of CDDP has been confirmed both experimentally and theoretically by other researchers 22 , 23 .…”

Section: Introductionsupporting

confidence: 65%

New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers

Zhang

2021

Sci Rep

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Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers. However, its clinical application is often limited by severe toxic side effects and drug resistance. Based on the discovered dissociative electron transfer mechanism of cisplatin, a novel combination of cisplatin with [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride (basic violet 10, BV10) is proposed to potentiate the chemotherapeutic effect of cisplatin. Here, we show that this combination enhances the anti-cancer effect of cisplatin in both in vitro cell lines and in vivo xenograft mouse models of cisplatin-sensitive and -resistant lung, ovarian and cervical cancers while introducing minimal additional toxic side effects. Furthermore, femtosecond time-resolved laser spectroscopic measurements demonstrate that cisplatin reacts with BV10 via an electron transfer mechanism. These results indicate that the combination of cisplatin with BV10 is promising for improving the chemotherapy of cancers with various extents of cisplatin resistance.

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Sensitizing DNA Towards Low‐Energy Electrons with 2‐Fluoroadenine

et al. 2016

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2-Fluoroadenine ( 2F A) is atherapeutic agent, which is suggested for application in cancer radiotherapy. The molecular mechanism of DNAr adiation damage can be ascribed to as ignificant extent to the action of low-energy (< 20 eV) electrons (LEEs), which damage DNAbydissociative electron attachment. LEE induced reactions in 2F Aa re characterized both isolated in the gas phase and in the condensed phase when it is incorporated into DNA. Information about negative ion resonances and anion-mediated fragmentation reactions is combined with an absolute quantification of DNAstrand breaks in 2F A-containing oligonucleotides upon irradiation with LEEs.T he incorporation of 2F A into DNAresults in an enhanced strand breakage.The strandbreak cross sections are clearly energy dependent, whereas the strand-break enhancements by 2F Aa t5 .5, 10, and 15 eV are very similar.T hus, 2F Ac an be considered an effective radiosensitizer operative at awide range of electron energies.Radiation therapy using high-energy photons,e lectrons,o r ions belongs to the most important methods used to treat cancer. As was shown in recent years,t he radiation damage induced by the high-energy primary radiation is mostly due to the effect of low-energy secondary particles generated along the ionization track. [1,2] Low-energy electrons (LEEs) belong to the most important intermediates,since they are produced in significant quantities [2,3] and can directly attach to DNA and other biomolecules to form transient negative ions,which are unstable towards dissociation. [4] In DNA, dissociative electron attachment (DEA) can result in effective single and double strand breaks. [5,6]

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A Single Slow Electron Triggers the Loss of Both Chlorine Atoms from the Anticancer Drug Cisplatin: Implications for Chemoradiation Therapy

Cited by 11 publications

References 17 publications

Hydrated Electrons React with High Specificity with Cisplatin Bound to Single-Stranded DNA

Hydrated Electrons React with High Specificity with Cisplatin Bound to Single-Stranded DNA

New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers

Sensitizing DNA Towards Low‐Energy Electrons with 2‐Fluoroadenine

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