195Pt NMR Kinetic and Mechanistic Studies of cis- and trans-Diamminedichloroplatinum(II) Binding to DNA.
About: This article is published in ChemInform.The article was published on 1990-12-25. It has received 47 citations till now. The article focuses on the topics: Cis–trans isomerism.
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TL;DR: Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations.
585 citations
Cites background from "195Pt NMR Kinetic and Mechanistic S..."
...Conversely, the reaction of platinum complexes with weaker nucleophiles, including the N(7) of guanines in the DNA, requires prior aquation [33, 34], which is achieved after interaction with both HCO3- and H2PO4- at physiological concentrations....
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...The subsequent dissociation of the second chloro ligand allows the conversion of the transiently formed monoadducts to a variety of stable diadducts [34, 42]....
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TL;DR: The structural information available for cisplatin and related platinumAdducts, the interactions of the adducts with cellular proteins and the implications of these interactions for cell survival are described.
Abstract: Cisplatin is a widely used chemotherapeutic agent. It reacts with nucleophilic bases in DNA and forms 1,2-d(ApG), 1,2-d(GpG) and 1,3-d(GpTpG) intrastrand crosslinks, interstrand crosslinks and monofunctional adducts. The presence of these adducts in DNA is through to be responsible for the therapeutic efficacy of cisplatin. The exact signal transduction pathway that leads to cell cycle arrest and cell death following treatment with the drug is not known but cell death is believed to be mediated by the recognition of the adducts by cellular proteins. Here we describe the structural information available for cisplatin and related platinum adducts, the interactions of the adducts with cellular proteins and the implications of these interactions for cell survival.
351 citations
Journal Article•
TL;DR: The results point to a potential new class of platinum antitumor complexes acting by a new mechanism and with activity complementary to agents such as cisplatin, as well as important biomolecules such as glutathione.
Abstract: The cytotoxicity of transplatinum complexes of structural formula trans-[PtCl2(L)(L')] [L = L' = pyridine or thiazole, or L = quinoline (R' = methyl; R" = methyl, phenyl, or CH2phenyl) and L' = R'R"SO] has been studied in murine L1210 and human tumor cell lines. The results confirm previous observations that use of a sterically hindered planar ligand greatly enhances cytotoxicity, in comparison to trans-[PtCl2(NH3)2], such that in some cases cytotoxicity equivalent to that of the clinically used agent cisplatin [cis-[PtCl2(NH3)2]] is obtained. Results from both the panel of human ovarian carcinoma cell lines and the National Cancer Institute screening panel confirm a different pattern of cytotoxicity, with respect to cisplatin. The new trans-platinum complexes are also non-cross-resistant with cisplatin in both murine and human (human ovarian carcinoma panel) tumor cell lines. Preliminary mechanistic studies using both cis- and trans-[PtCl2(pyridine)2] in L1210 cells have been carried out, to delineate the reasons for both the dramatically enhanced cytotoxicity and the lack of cross-resistance with the clinically used agents. Intracellular uptake is enhanced for pyridine relative to ammine (NH3) complexes. The pyridine complexes also inhibit DNA synthesis, implying a role for DNA binding in their mechanism of action. Binding of the pyridine complexes to calf thymus DNA is, however, significantly less than for the analogous ammine complexes. The presence of trans-pyridine ligands results in steric hindrance, which retards the rate of reaction of trans-[PtCl2(pyridine)2], relative to trans[PtCl2(NH3)2], with other important biomolecules such as glutathione. The results point to a potential new class of platinum antitumor complexes acting by a new mechanism and with activity complementary to agents such as cisplatin.
174 citations
TL;DR: Comparison of common features and differences between different classes may point to guidelines for the rational design of complexes with a different spectrum of clinical antitumor activity to cisPlatin and activity against cisplatin-resistant tumors.
Abstract: (1993). Nonclassical Platinum Antitumor Agents: Perspectives for Design and Development of New Drugs Complementary to Cisplatin. Cancer Investigation: Vol. 11, No. 5, pp. 578-589.
107 citations
TL;DR: Experiments with Pt(dach)Cl2 indicate that oxaliplatin may modify the DNA structures in the same way as cisplatin, and a model is proposed to explain this kind of DNA condensation by cis Platin: first, di-adducts induce local distortions of DNA, then large aggregates are formed through further crosslinks, and DNA is condensed into a compact globule.
Abstract: Structural properties of single lambda DNA treated with anti-cancer drug cisplatin were studied with magnetic tweezers and AFM. Under the effect of low-concentration cisplatin, the DNA became more flexible, with the persistence length decreased significantly from approximately 52 to 15 nm. At a high drug concentration, a DNA condensation phenomenon was observed. Based on experimental results from both single-molecule and AFM studies, we propose a model to explain this kind of DNA condensation by cisplatin: first, di-adducts induce local distortions of DNA. Next, micro-loops of approximately 20 nm appear through distant crosslinks. Then, large aggregates are formed through further crosslinks. Finally, DNA is condensed into a compact globule. Experiments with Pt(dach)Cl(2) indicate that oxaliplatin may modify the DNA structures in the same way as cisplatin. The observed loop structure formation of DNA may be an important feature of the effect of platinum anti-cancer drugs that are analogous to cisplatin in structure.
106 citations
Cites background from "195Pt NMR Kinetic and Mechanistic S..."
...When the aqueous cisplatin reacts with DNA, its water molecules are easily substituted by the N7 atoms of guanine or adenine to form both mono-adduct and di-adduct (4,5)....
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References
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TL;DR: The kinetics and mechanism of binding of the anticancer drug cis-diamminedichloroplatinum(II), or cis-DDP, and its inactive trans isomer to chicken erythrocyte DNA at 37 o C have been investigated by 195 Pt NMR spectroscopy.
Abstract: The kinetics and mechanism of binding of the anticancer drug cis-diamminedichloroplatinum(II), or cis-DDP, and its inactive trans isomer to chicken erythrocyte DNA at 37 o C have been investigated by 195 Pt NMR spectroscopy. Both cis-and trans-DDP bind to DNA by two successive pseudo-first-order processes, forming monofunctional adducts ( 195 Pt NMR shifts near -2300 ppm) that subsequently close to bifunctional lesions (chemical shifts near -2450 ppm)
458 citations