Journal ArticleDOI
Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation
Anne Marie J. Fichtinger-Schepman,J. L. Van Der Veer,J. H. J. Den Hartog,P. H. M. Lohman,Jan Reedijk +4 more
TLDR
In kinetic studies on the formation of the various adducts, a clear preference of the Pt compound to react with guanines occurring in the base sequence d(pGpG) was established and the method was used to optimize the digestion conditions for cis-DDP-treated DNA.Abstract:
Salmon sperm DNA, treated with the antitumor agent cis-diamminedichloroplatinum(II) (cis-DDP), was enzymatically degraded to (oligo)nucleotides. Four Pt-containing products were identified by 1H NMR after preparative chromatography on a diethylaminoethyl-Sephacel column at pH 8.8. In all identified adducts, comprising approximately 90% of the total Pt in the DNA, Pt was linked to the N7 atoms of the nucleobases guanine and adenine. The two major adducts were cis-Pt(NH3)2d(pGpG) and cis-Pt-(NH3)2d(pApG), both derived from intrastrand cross-links of cis-DDP on neighboring nucleobases. Only the d(pApG) but not the d(pGpA) adduct could be detected. Two minor adducts were Pt(NH3)3dGMP, resulting from monofunctionally bound cis-DDP to guanine, and cis-Pt(NH3)2d(GMP)2, originating from interstrand cross-links on two guanines as well as from intrastrand cross-links on two guanines separated by one or more bases. For analytical purposes we developed an improved method to determine cis-DDP adducts. Routinely, 40-micrograms samples of enzymatically degraded cis-DDP-treated DNA are now analyzed by separation of the mononucleotides and Pt-containing (oligo)nucleotides on the anion-exchange column Mono Q (FPLC) at pH 8.8 (completed within 14 min) and subsequent determination of the Pt content in the collected fractions by atomic absorption spectroscopy. The method was used to optimize the digestion conditions for cis-DDP-treated DNA. In kinetic studies on the formation of the various adducts, a clear preference of the Pt compound to react with guanines occurring in the base sequence d(pGpG) was established.read more
Citations
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The resurgence of platinum-based cancer chemotherapy
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The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs
TL;DR: Recently, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs as mentioned in this paper.
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Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals
TL;DR: It is demonstrated that deletion of the yeast CTR1 gene, which encodes a high-affinity copper transporter, results in increased cis platin resistance and reduced intracellular accumulation of cisplatin, and proposed that cisplin uptake is mediated by the copper transporter Ctr1p in yeast and mammals.
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Mechanisms of resistance to cisplatin.
Maria Kartalou,John M. Essigmann +1 more
TL;DR: An improved understanding of the mechanisms of resistance operative in vivo has identified targets for intervention and may increase the utility of cisplatin for the treatment of cancer.
References
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Journal ArticleDOI
Characterization of the adducts produced in DNA by cis-diamminedichloroplatinum(II) and cis-dichloro(ethylenediamine)platinum(II).
Journal ArticleDOI
New chemistry of an old molecule: cis-[Pt(NH3)2Cl2]
TL;DR: The discovery that cis-diamminedichloroplatinum(II) (cis-DDP) has clinically useful antitumor properties and can form platinum blues spawned an extensive investigation of its chemistry in water.
Journal Article
Induction and repair of DNA cross-links in chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicity, and antitumor activity.
Plooy Ac,van Dijk M,Lohman Ph +2 more
TL;DR: As the slow repair of the cis-platinum-induced interstrand and DNA-protein cross-links leads to a certain persistency of these adducts, the unrepaired lesions might be responsible for cytotoxicity, mutagenicity, and antitumor activity.
Journal ArticleDOI
Detection and quantification of adducts formed upon interaction of diamminedichloroplatinum (II) with DNA, by anion-exchange chromatography after enzymatic degradation
TL;DR: A method has been developed to determine the adducts formed upon interaction of cis- and trans-diamminedichloroplatinum(II) (cis- andTrans-DDP) with DNA, which could be derived from intrastrand crosslinks between two guanines at sites with pGpXpG (X=T,C,A or G) base sequences.
Journal ArticleDOI
Base-pair substitution hotspots in GAG and GCG nucleotide sequences in Escherichia coli K-12 induced by cis-diamminedichloroplatinum (II)
TL;DR: Examination of the nature of the mutations induced by cis-Pt(NH3)2Cl2, by using the LacI system, revealed that base-pair substitutions leading to nonsense mutants are only induced in wild-type cells, suggesting that the intact products of both the uvrB and the recA gene are necessary for the repair responsible for this type of mutagenesis.