Cisplatin interactions

Cisplatin is one of the most effective and broadly used anticancer drugs and it is particularly useful for the treatment of testicular cancer [1], Cisplatin interacts with cellular DNA, RNA and proteins [2-4], Interaction of cisplatin with DNA forms several classes of DNA adducts [3]. DNA adducts are generally considered to be responsible for the toxicity and mutagenicity of cisplatin, although its biological activity cannot be solely explained by its ability to damage DNA [4],... 

Other applications of 31P line shape analysis, including study of cisplatin interaction with the PS headgroup,109 description coating of polyelectrolyte particles... 

Briichert, W., Kruger, R., Tholey, A., Montes-Bayon, M., Bettmer, J. A novel approach for analysis of oligonucleotide-cisplatin interactions by continuous elution gel electrophoresis coupled to isotope dilution inductively coupled plasma mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry. Electrophoresis 29, 1451-1459 (2008)... 

Klein J, Bentur Y, Cheung D, Moselhy G, Koren G. Renal handling of cisplatin interactions with organic anionas and cations in the dog. Clin Inv Med 1991 14 388-394. 

Cisplatin is incompatible in solutions having low chloride content. Cisplatin interacts with aluminum, and only administration equipment that does not contain aluminum should be used for this medication. When heated to decomposition, toxic fumes of hydrogen chloride and nitrogen oxide are emitted. 

Similarly, the rate constants for cisplatin interactions with guanine were estimated. In these studies either water replacement by the base (kPI a kP2) or hydration process of the already coordinated cisplatin with guanine (k3) were considered ... 

The cis isomer ( cisplatin ) is an effective anticancer drug. This reflects the ability of the two Cl atoms to interact with the nitrogen atoms of DNA, a molecule responsible for cell reproduction. The trans isomer is ineffective in chemotherapy, presumably because the Q atoms are too far apart to react with a DNA molecule. 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

Recent reviews in the field of platinum anticancer drugs focus on platinum-nucleobase chemistry [7], biological processing of platinum-modified DNA [8], trans-platinum anticancer drugs [5], cisplatin and derived anticancer drugs [4,9], proteins and cisplatin [10], trans-diam-mineplatinum(II) and nucleic acids [11], and catalytic activity and DNA [12], just to mention a few. The aim of this review is to explore the chemistry in the interaction of various platinum compounds with nucleic... 

The conversion of the monofunctional adducts into bifunctional lesions depends drastically on the structure of the Pt drug. Obviously, Pt compounds exhibiting trans geometry form different bisadducts than cisplatin and hence, a different spectrum of antitumor activity is expected. Mechanistically, the formation and possible isomerization of bisadducts are not well understood. The assumption that hydrolysis of the second leaving group controls the formation of bisadduct may be an oversimplification. Studies with model compounds as well as with oligonucleotides have indicated that a certain nucleobase may be a powerful nucleophile toward Pt(II) if spatially in a correct position. Unfortunately, our knowledge on these interactions is at present very limited. 

Two examples of aquation/anation studies of chloro-platinum(II) complexes of possible medical relevance appeared in subsection 1 above 202,207). Aquation of cisplatin is slower in the presence of DNA but not in the presence of phosphate 220). DNA also inhibits substitution in [Pt(terpy)(py)]2+ and related complexes. For reaction of these charged complexes with iodide ion inhibition is attributable to electrostatic interactions - the complex is concentrated on the double helix and thus separated from the iodide, which distances itself from the helix. Intercalation of these complexes within the helix also serves to make nucleophilic approach by neutral reagents such as thiourea more difficult 221). 

Glutathione readily replaces the GSMe on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylglutathione) - this system is claimed to be an effective model for cisplatin-protein interaction 224). Rate constants and activation parameters have been... 

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