Journal of inorganic biochemistry
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Review
Platinum neurotoxicity: clinical profiles, experimental models and neuroprotective approaches.
This paper reviews the neurotoxic side-effects associated with platinum drugs, experimental approaches to studying this toxicity and attempts to use neuroprotective agents in conjunction with platinum drugs. Platinum drugs differ in their neurotoxicity profiles in patients. ⋯ Animal models, primary cultures of dorsal root ganglia neurons and tumour cell-lines of neuronal origin are being used in attempts to identify potential treatments for platinum-induced neurotoxicity. To date, clinical trials have been hampered by the poor tolerance of neuroprotective treatments and failure to achieve reversal of platinum drug neurotoxicity with thiols, neurotrophic factors or calcium channel blockers.
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A reactive Cr(IV) ester was synthesized from a reaction of CrO3 with 2,4-dimethyl-2,4-pentanediol as verified by electron spin resonance (ESR) and magnetic susceptibility measurements. ESR spin trapping studies demonstrate that the Cr(IV) ester is capable of generating hydroxyl free radical (. OH) through a Fenton-like mechanism (Cr(IV)+H2O2-->Cr(V)+. ⋯ The results demonstrate that Cr(IV) and its generated. OH radicals are capable of damaging DNA. Moreover, in comparison with Cr(V), Cr(IV) is a more potent DNA damaging agent.
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Electron spin resonance (ESR) measurements provide evidence for the formation of Cr(V) intermediates in the enzymatic reduction of Cr(VI) by glutathione reductase (GSSG-R) in the presence of NADPH, indicating an initial single-electron transfer step in the reduction mechanism. Depending on the pH, at least two different Cr(V) species are generated which are relatively long-lived. In addition, we have detected the hydroxyl (. ⋯ OH radical formation. Measurements involving N-ethylmaleimide show that the Cr(V) species, produced enzymatically by the reduction of Cr(VI) by GSSG-R, react with H2O2 to generate. OH radicals, which might participate in the initiation of Cr(VI) carcinogenicity.