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Platinum-sulfur interactions

Since the discovery of ds-Pt as an antitumor drug, the research on the mechanism of action has mainly been focused on the interactions with DNA, as summarized in the preceding section. Although such interac- [Pg.189]

The reaction of sulfur-containing biomolecules with platinum antitumor compounds, thereby preventing binding to the critical DNA target, is a possible mechanism of inactivation and is supported by numerous studies. Thus, glutathione (GSH, a cysteine-containing tripeptide see also Fig. 6), which is the predominant intracellular thiol and is present in concentrations varying from 0.5 to 10 mM, is able to inhibit the reaction of DNA with [Pt(en)Cl2] (74) and with cis-Pt (75, 76). It has also been observed that the presence of cysteine can inhibit the reaction between cis-Pt and d-Guo (77). Furthermore, the antitumor activity of cis-Pt was proved to be inhibited by coadministered methionine (78, 79) and even a bis-adduct between cis-Pt and methionine has been isolated from the urine of patients (80). [Pg.190]

The reactions of cis- and trans-Pt have been recently investigated with the use of 1H NMR by Berners-Price and Kuchel (81) in intact [Pg.190]

A second mechanism of inactivation might be the reaction of sulfur-containing biomolecules with the cis-Pt-DNA monoadducts (product 1 in Fig. 4), which prevents those from rearranging to toxic bifunctional adducts. Supportive for such a mechanism is the observation that GSH can be cross-linked to DNA by cis-Pt (41,41a) and [Pt(en)Cl2] (74), and that cysteine can be cross-linked to d-Guo by cis-Pt (77). Furthermore, cis-Pt-DNA monoadducts can be experimentally quenched with thiourea, which reduces drug toxicity (82, 83). trans-Pt also yields monofunctional adducts after reaction with DNA, and these rearrange somewhat slower than does cis-Pt into bifunctional adducts (41,84), clearly for sterical reasons. The relatively long-living monofunctional adducts react efficiently with GSH and proteins (41 a, 84-86). [Pg.191]

The clinical usefulness of cis-Pt is often limited by the development of resistance. The development of resistance to cis-Pt has been explained by several factors, including reduced drug accumulation, increased DNA repair processes, and an increase in the amount of inactivation proteins. In most cis-Pt-resistant tumors probably a combination of such factors plays a role. In this section, only an increase in cellular thiols in relation to resistance will be discussed. Such inactivation processes have already been discussed (Section IV,B), but attention will be directed now to the mechanism of resistance. These mechanisms are probably also of importance for the inactivation of cis-Pt in nonre-sistant tumors, though to a lesser extent. [Pg.192]


Platinum-Sulfur Interactions Involved in Antitumor Drugs, Rescue Agents, and Biomolecules... [Pg.182]

J. Reedijk and J. M. Teuben, Platinum - Sulfur Interactions Involved in Antitumor Drugs, Rescue Agents, and Biomolecules, in 30 Years of Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug , ed. B. Lippert, Wiley VCH, Weinheim, 1999, p. 339. [Pg.3888]

Extended Htickel calculations have been used to analyze the electronic structure of platinum complexes and also to rationalize their reactivity with various nucleophiles. Their inability to form four coordinate species of the type [Pt(S2CNR2)(ri -S2CNR2)2] has been ascribed to the lower charge on platinum (when compared with xanthate complexes), strong platinum-sulfur bonds and a repulsive interaction between the platinum 2>d electrons and the incoming ligand (1601). [Pg.364]

R SiH and CH2= CHR interact with both PtL and PtL 1. Complexing or chelating ligands such as phosphines and sulfur complexes are exceUent inhibitors, but often form such stable complexes that they act as poisons and prevent cute even at elevated temperatures. Unsaturated organic compounds are preferred, such as acetylenic alcohols, acetylene dicarboxylates, maleates, fumarates, eneynes, and azo compounds (178—189). An alternative concept has been the encapsulation of the platinum catalysts with either cyclodextrin or in thermoplastics or siUcones (190—192). [Pg.48]

Nickel and selenium interact with incandescence on gentle heating [1], as do also sodium and potassium, the latter mildly explosively [2], Uranium [3] and zinc [4] also incandesce when their mixtures with selenium are heated, and platinum sponge incandesces vividly [5], The particle size of cadmium and selenium must be below a critical size to prevent explosions during synthesis of cadmium selenide by heating the elements together. Similar considerations also apply to interaction of cadmium or zinc with sulfur, selenium or tellurium [6], Interaction of powdered tin and selenium at 350° C is extremely exothermic [7],... [Pg.1907]

INTERACTIONS OF PLATINUM AMINE COMPOUNDS WITH SULFUR-CONTAINING BIOMOLECULES AND DNA FRAGMENTS... [Pg.175]

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). [Pg.201]

Interactions of platinum amine complexes with sulfur-containing biomolecules and DNA fragments. Adv. Inorg. Chem. Radioehem. 37, 175 (1991). [Pg.164]

Gasolines contain a small amount of sulfur which is emitted with the exhaust gas mainly as sulfur dioxide. On passing through the catalyst, the sulfur dioxide in exhaust gas is partially converted to sulfur trioxide which may react with the water vapor to form sulfuric acid (1,2) or with the support oxide to form aluminum sulfate and cerium sulfate (3-6). However, sulfur storage can also occur by the direct interaction of SO2 with both alumina and ceria (4,7). Studies of the oxidation of SO2 over supported noble metal catalysts indicate that Pt catalytically oxidizes more SO2 to SO3 than Rh (8,9) and that this reaction diminishes with increasing Rh content for Pt-Rh catalysts (10). Moreover, it was shown that heating platinum and rhodium catalysts in a SO2 and O2 mixture produces sulfate on the metals (11). [Pg.345]


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See also in sourсe #XX -- [ Pg.189 , Pg.190 , Pg.191 , Pg.192 , Pg.193 , Pg.194 , Pg.195 , Pg.196 , Pg.197 , Pg.198 , Pg.199 , Pg.200 , Pg.201 , Pg.202 , Pg.203 , Pg.204 , Pg.205 , Pg.208 ]




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