Unwinding of supercoiled DNA by platinum-ethidium and related complexes

Keck, Michael; Lippard, Stephen J.

doi:10.1021/ja00035a033

Cited by 301 publications

(361 citation statements)

References 6 publications

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“…The initial decrease of Form I mobility, followed by co-migration with Form II, then increased mobility, corresponds with trends seen for both cisplatin (9,21,22) and carboplatin (5,6) in previous gel electrophoresis studies. Using carbonate-activated carboplatin at low concentration, we were able to see migration patterns which were only observed using lengthy incubation times (6) or much higher drug concentrations (5) Our observations with carboplatin showed some key differences compared with earlier cisplatin studies.…”

Section: Discussionsupporting

confidence: 87%

“…and Form II migrate to the same point on the gel) occurs at r = 1.4, this point does not seem to correspond to the migration for DNA with zero supercoiling (Form II when r = 0.0) as it did for Keck and Lippard (9). Second, the staining intensity trends seen here differ from those found in cisplatin studies (21).…”

Section: Discussioncontrasting

confidence: 69%

“…Carboplatin's bidentate dicarboxylate chelate makes the drug much less reactive than cisplatin, which may partly explain the reduction in side effects seen in chemotherapy (7). Electrophilic platinum compounds have been shown to bind DNA in the cell, forming mono-and bifunctional adducts (7)(8)(9). It is generally thought that such DNA lesions induce apoptosis, destroying cancerous cells, though other mechanisms of action have been proposed (10).…”

Section: Introductionmentioning

confidence: 99%

“…By carrying out DNA binding in a carbonate-rich solution, we modeled the environment of cellular DNA in vivo. We used closed-circular plasmid DNA as our binding target, and measured the extent of binding through agarose gel electrophoresis, a benchmark technique in the study of platinum-DNA binding (5,6,9). We found that physiologically-relevant concentrations of carbonate in the DNA environment prevented binding of carbonate-aged carboplatin.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Carbonate on the Binding of Carboplatin to DNA

Sorokanich

Pasqua

Geier

et al. 2008

Chemistry & Biodiversity

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The reaction of aged carboplatin (reaction of carboplatin in 24 mM NaHCO 3 for 45 h, 37 o C, pH 8.6) with pBR322 DNA for 0 ≤ r ≤ 2.8, where r = [drug]/ [DNAbp], in 24 mM HEPES buffer, pH 7.4, for 24 h followed by agarose gel electrophoresis showed DNA mobility changes consistent with unwinding closed circular DNA. However, identical experiments conducted in a two buffer system, 24mM HEPES plus 24mM carbonate, showed no DNA mobility changes, indicating that carbonate blocks formation of the 1,2-intrastrand crosslink on DNA. Studies with aged carboplatin and with cisplatin carried out with 2.0 ≤ r ≤ 10.0 in the two buffer system show that some DNA binding and unwinding occurs for both drugs. Since carbonate inhibits the binding of aged carboplatin and cisplatin to DNA, carbonate present in the body likely modulates the reactivity of these drugs with a variety of biological targets including DNA.

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Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Carbonate on the Binding of Carboplatin to DNA

Sorokanich

Pasqua

Geier

et al. 2008

Chemistry & Biodiversity

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“…Unwinding of closed circular supercoiled pUC19 plasmid DNA was assayed by an agarose gel mobility shift assay. 29 The mean unwinding angle can be and KPF 6 were added. All the synthesized complexes were fully characterized by spectroscopic and analytical methods.…”

Section: Methodsmentioning

confidence: 99%

Photoactivatable Organometallic Pyridyl Ruthenium(II) Arene Complexes

et al. 2012

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The synthesis and characterization of a family of piano-stool Ru II arene complexes of the type [(η 6 -arene)Ru(N,N')(L)] [PF 6 ] 2 where arene is para-cymene (p-cym), hexamethylbenzene (hmb) or indane (ind); N,N' is 2,2'-bipyrimidine (bpm), 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione (phendio), 4,7-diphenyl-1,10-phenanthroline (bathophen), and L is pyridine (Py), 4-methylpyridine (4-MePy), 4-methoxypyridine (4-MeOPy), 4,4'-bipyridine (4,4'-biPy), 4-phenylpyridine (4-PhPy), 4-benzylpyridine (4-BzPy), 1,2,4-triazole (trz), 3-acetylpyridine (3-AcPy), nicotinamide (NA), or 3-acetatepyridine (3-AcOPy) are reported; including the X-ray crystal structures of [(η 6 -p-[(η 6 -p-cym)Ru(phen)(Py)] 2+ (10), and [(η 6 -ind)Ru(bpy)(Py)] 2+ (13). These complexes can selectively photodissociate the monodentate ligand (L) when excited with UVA or white light allowing strict control of the formation of the reactive aqua species [(η 6 -arene)Ru(N,N')(OH 2 )] 2+ that otherwise would not form in the dark. The photoproducts were characterized by UV-vis absorption and 1 H NMR spectroscopy. DFT and TD-DFT calculations were employed to characterize the excited states and to obtain information on the photochemistry of the complexes. All the Ru II pyridine complexes follow a relatively similar photochemical L-ligand dissociation mechanism, likely to occur from a series of 3 MC triplet states with dissociative character. The photochemical process proved to be much more efficient when UVA-range irradiation was used. More strikingly, light activation was used to photo-trigger binding of these potential anticancer agents with discriminating preference towards 9-ethylguanine (9-EtG) over 9-ethyladenine (9-EtA). Calf-thymus (CT)-DNA binding studies showed that the irradiated complexes bind to CT-DNA whereas the non-irradiated forms, bind negligibly.

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Cisplatin

2009

Metals in Medicine

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3 Cisplatin Cisplatin, cis-diamminedichloroplatinum(II), a square planar Pt 2þ complex (Figure 3.1), was the first metalbased agent to enter into worldwide clinical use for the treatment of cancer. Currently, cisplatin is used either by itself or in combination with other drugs for treating lung, ovarian, bladder, testicular, head and neck, esophageal, colon, gastric, breast, melanoma and prostate cancer. Although sales of cisplatin are presently on the decline, with second-and third-generation analogs being more widely prescribed, cisplatin remains the 'gold standard' to which aspiring platinum and nonplatinum metal-based anticancer drugs are compared.While it is not possible to cover the more than 40 years of research on cisplatin in one chapter, the important physical and chemical properties of the drug, aspects of its clinical applications and pharmacokinetics, as well as its biological mechanism of action will be presented and discussed here. More information on cisplatin regarding these and other topics can be found in the excellent books, review articles and publications of Rosenberg [1,2], Lippard [3-5], Reedijk [6,7], Farrell [8], Kelland and Farrell [9], Lippert [10], Hambley [11,12], Sadler [13], Schellens [14,15] and Boulikas and Vougiouka [16], and their coworkers. Box 3.1 Discovery of cisplatinThe idea of investigating the antitumor properties of cisplatin was based on an accidental discovery made by Barnett Rosenberg, a professor of biophysics at Michigan State University, and his coworkers in the early 1960s [2,11,17,18]. Professor Rosenberg was studying the effects of electric fields on the growth of cells and he and his group constructed a special cell culture apparatus containing platinum mesh electrodes that allowed cells to grow and be harvested on a continuous basis. The goal of the study was to apply alternating currents of different frequencies to the electrodes and determine whether and to what extent electric current affected the ability of the cells to divide. While the investigators were really interested in mammalian cells, they tested the new apparatus using E. coli bacteria and found to their surprise that certain frequencies of current greatly reduced the number of cells growing in the culture apparatus. A check on the appearance of the bacteria that had been subjected to electric current revealed that bacterial cells were present but instead of having their normal 'sausage' shape, they were long spaghetti-like filaments, which indicated that the cells were growing but not dividing. Sensing that they were observing something new and very unusual, the investigators carried out a number of control experiments which showed that, while the electric current itself had no direct effect on cell division, the current was causing a chemical reaction to take place in the cell culture medium, which required oxygen, ammonium ion (NH 4 þ ) and chloride ion (Cl À ). After learning this, and after realizing that the current was causing a small amount of platinum metal on the surface of the electr...

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Unwinding of supercoiled DNA by platinum-ethidium and related complexes

Cited by 301 publications

References 6 publications

Influence of Carbonate on the Binding of Carboplatin to DNA

Influence of Carbonate on the Binding of Carboplatin to DNA

Photoactivatable Organometallic Pyridyl Ruthenium(II) Arene Complexes

Cisplatin

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