Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem Toxicol

Department of Medicine, Sultan Qaboos University, Masqaţ, Muḩāfaz̧at Masqaţ, Oman
Food and Chemical Toxicology (Impact Factor: 2.9). 09/2006; 44(8):1173-83. DOI: 10.1016/j.fct.2006.01.013
Source: PubMed


Cisplatin (cis-diamminedichloroplatinum (II)) is an effective agent against various solid tumours. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.g. carboplatin, oxaliplatin, nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the effectiveness and to lessen the toxicity of cisplatin. Several agents have been tested to see whether they could ameliorate or augment the nephrotoxicity of platinum drugs. This review summarizes these studies and the possible mechanisms of actions of these agents. The agents that have been shown to ameliorate experimental cisplatin nephrotoxicity include antioxidants (e.g. melatonin, vitamin E, selenium, and many others), modulators of nitric oxide (e.g. zinc histidine complex), agents interfering with metabolic pathways of cisplatin (e.g. procaine HCL), diuretics (e.g. furosemide and mannitol), and cytoprotective and antiapoptotic agents (e.g. amifostine and erythropoietin). Only few of these agents have been tested in humans. Those agents that have been shown to augment cisplatin nephrotoxicity include nitric oxide synthase inhibitors, spironolactone, gemcitabine and others. Combining these agents with cisplatin should be avoided.

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Available from: Badreldin H. Ali, May 22, 2015
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    • "Cisplatin forms strong electrophilic intermediates that act via nucleophilic substitution reactions to form inter-and intra-strand DNA cross-links. The mechanism of action of this drug involves entering the cell, where Cl À dissociates, leaving a reactive complex that reacts with water and then interacts with DNA (Ali and Al Moundhri, 2006). However, beside its potent antitumor activity, cisplatin has serious adverse effects on kidney, heart, liver, as well as reproductive, gastrointestinal and nervous systems (Dasari and Tchounwou, 2014). "
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    ABSTRACT: The aim of this study was to evaluate the effects of chronic NAC administration along with cisplatin on cisplatin-induced cardiotoxicity by means of coronary flow (CF), cardiodynamic parameters, oxidative stress markers and morphological changes in isolated rat heart. Isolated hearts of Wistar albino rats (divided into four groups: control, cisplatin, NAC and cisplatin+NAC group) were perfused according to Langendorff technique at constant coronary perfusion pressure starting at 50 and gradually increased to 65, 80, 95 and 110cm H2O to evaluate cardiodynamic parameters within autoregulation range. Samples of coronary venous effluent (CVE) were collected for determination of CF and biochemical assays, and heart tissue samples for biochemical assays and histopathological examination. Cisplatin treatment decreased CF and heart rate, and increased left ventricular systolic pressure and maximum left ventricular pressure development rate. Cisplatin increased H2O2 and TBARS, but decreased NO2(-) levels in CVE. In tissue samples, cisplatin reduced pathological alterations in myocardium and coronary vessels, with no changes in the amount of total glutathione, as well as in activity of glutathione peroxidase and glutathione reductase. NAC coadministration, by reducing oxidative damage, attenuated cisplatin-induced changes of cardiodynamic and oxidative stress parameters, as well as morphological changes in myocardium and coronary vasculature.
    Full-text · Article · Nov 2015 · Toxicology Letters
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    • "Cisplatin, or cis-diamminedichloroplatinum (II), is one of the most effective water-soluble chemotherapeutic drugs, which is formed when a platinum atom is surrounded by chloride and ammonium atoms in the cis positions of a horizontal plane [1]. Although cisplatin is used to treat a wide variety of tumors, its use is limited because of adverse side effects such as ototoxicity, neuropathy , and gastrointestinal damage [2e4]. "
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    ABSTRACT: Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage.
    Full-text · Article · Oct 2015 · Biochemical and Biophysical Research Communications
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    • "This result is also consistent with (Nabila et al., 2008), who found a strong positive correlation between the content of total phenolics and FRAP assay. All of these studies were based on the assumption that GA has strong anti-oxidant, and a major mechanism for the induction of these toxicities is the generation of free radicals (Benzie and Stezo., 1999) and (Ali and Al Moundhri ., 2006). "

    Full-text · Article · Aug 2015
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