Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug

Zunino, Franco; Pratesi, Graziella; Micheloni, Antonella; Cavalletti, Ennio; Sala, Federica; Tofanetti, O.

doi:10.1016/0009-2797(89)90065-3

Cited by 149 publications

(54 citation statements)

References 20 publications

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“…Experimental and clinical studies have shown that GSH is neuro-and nephroprotective (Hamers ef al. 1993;Zunino et al 1989;Fontanelli et a/ 1992). Other studies have also demonstrated the importance of intracellular GSH for protection against heavy metal toxicity Singhal et a/.…”

Section: Discussionmentioning

confidence: 98%

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Rybak

Husain

Evenson

et al. 1997

Pharmacology & Toxicology

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Ahsfracf: This study was undertaken in order to determine the changes in auditory brainstem-evoked responses relationship with the changes in the levels of GSH, lipid peroxidation and antioxidant enzymes activity in cisplatin-induced ototoxicity and otoprotection by 4-methylthiobenzoic acid (MTBA). Male Wistar rats in different groups were treated as follows: 1) saline control; 2) cisplatin ( I 6 mg/kg. intraperitoneally); 3 ) MTBA (250 mg/kg, intraperitoneally), and 4) cisplatin plus MTBA. Post-treatment auditory brainstem-evoked responses were performed after three days and the rats were sacrificed and cochleae harvested. The cochleae were analyzed for glutathione (GSH), antioxidant enzyme activity, and malondialdehyde levels. The cisplatin injected rats showed a threshold elevation of 31.95 16.0 dB above the pretreatment thresholds using click stimulus. Rats treated with MTBA plus cisplatin did not show significant elevation of hearing threshold. Cisplatin plus MTBA administration showed a higher levels of cochlear GSH (5.59t0.35 nmoles/mg protein) compared to cisplatin alone (4.46?0. I3 nmolesimg protein). Cisplatin treated rats showed a decrease in superoxide dismutase, catalase, glutathione peroxidase (GSH-peroxidase), and glutathione reductase (GSH-reductase) activities (57"h. 83'%1, 78% and 58's of control). Cochlear superoxide dismutase, catalase and GSH-reductase activities and MDA levels were restored in the rats injected with cisplatin plus MTBA, compared to cisplatin alone. It is concluded that the protection conferred by MTBA against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant system. Cisplatin (cis-diamminedichloroplatinum) is currently being used clinically as an effective antitumour agent against a variety of neoplasms, but its use is limited by the onset of side effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. High doses of cisplatin result in profound deafness (Rybak 1981; Fausti et al. 1984Fausti et al. & 1993Powis & Hacker 1991). The severity of these toxic side-effects remains an obstacle to the clinical use of high-dose cisplatin. To identify safer methods of cisplatin dose escalation, the use of chemoprotectors has been explored. al. 1992). procaine (Zhang et al. 1992), and other sulfur containing compounds (Basinger et al. 1990;Jones et al. 1991Jones et al. & 1992. The rationale for their use is the high affinity of sulfur ligands for platinum complexes.Clinical and experimental studies have demonstrated that administration of GSH is nephro-and neuroprotective but its role in otoprotection is unclear (Zunino P t al. 1989;Fontanelli et al. 1992;Hamers et a/. 1993 et ul. 1986;Zunino et a/. 1983;Hamers et al. 1993). However, the effect of GSH level in relation to ototoxicity is unknown.Ototoxicity is the dose-limiting side effect following diethyldithiocarbamate chemoprotection (Berry et 01. 1990). Preliminary results in clinical studies by Gandara et (11. (1990 & 1991) suggest possible protection against ototoxicity by diethyldit...

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Section: Discussionmentioning

confidence: 98%

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Rybak

Husain

Evenson

et al. 1997

Pharmacology & Toxicology

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“…The timing of CDDP administration after NAC becomes an issue, due to the rapid clearance of NAC . Glutathione protection against CDDP-induced nephrotoxicity was found to be critically dependent on timing of thiol administration (Zunino et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Protection against Cisplatin-Induced Toxicities byN-Acetylcysteine and Sodium Thiosulfate as Assessed at the Molecular, Cellular, and in Vivo Levels

Dickey

Muldoon³

et al. 2005

J Pharmacol Exp Ther

201

178

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Cisplatin (CDDP) is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo CDDP toxicities. For ototoxicity studies, CDDP (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. Auditory brainstem response thresholds at 4 to 20 kHz were tested before and 7 days post-treatment. STS (8 g/m 2 i.v.) was administered at 4, 8, or 12 h after CDDP. For nephrotoxicity studies, rats were treated with CDDP intraperitoneally (10 mg/kg) before or after NAC (400 mg/kg) or STS (8 g/m 2 ), and blood urea nitrogen (BUN) and creatinine concentrations were measured after 3 days. In vitro cytotoxicity and chemoprotection in human tumor cell lines were assessed by cell viability and immunoblotting assays. Rats treated with STS 4 h after CDDP exhibited no hearing change. The STS 8-h group had less otoprotection, whereas 12-h rats had ototoxicity. CDDP induced high BUN and creatinine, corresponding to renal tubule toxicities. All NAC-treated animals showed normal BUN and reduced creatinine levels compared with CDDP alone and no histopathological evidence of nephrotoxicity. Delayed STS treatment was not consistently protective against nephrotoxicity. STS administration fully protected against the in vitro cytotoxic and apoptotic effects of CDDP if added within 2 h of CDDP, but chemoprotection decreased if STS administration was 4 h, and was minimal by 6 h, after CDDP. Thus, the chemoprotection route and timing of administration can be manipulated to maintain CDDP antitumor efficacy while protecting against toxicities.

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“…The use of hydration, hypertonic saline, diuretics, and other chemotherapeutic agents has rendered protection against cisplatin-induced nephrotoxicity (Tognella 1990) and enabled the use of higher doses of cisplatin. Protective agents being evaluated against nephrotoxicity in experimental and clinical studies include diethyldithiocarbamates (Qazi et al 1988;Hidaka et al 1994;Walker et al 1994;Somani et al 1995), sodium thiosulfate (Markman et al 1991), S-2-(3-aminopropylamino)-ethyl phosphorothioic acid (WR2721) (Yuhas & Culo 1980), glutathione (GSH, and its esters) (Zunino et al 1989;Fontanelli et al 1992;Babu et al 1995), glycine (Heyman et al 1993), methionine (Basinger et al 1990), thioether (Boogaard et al 1991;Jones et al 1991;Husain et al 1996), procaine and procainamide (Esposito et al 1990(Esposito et al & 1996. Most of the compounds that ameliorated the cisplatin-induced nephrotoxicity contain a nucleophilic sulphur atom that probably forms a coordinate bond to the platinum ion.…”

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confidence: 99%

“…We have earlier reported that free radical-mediated oxidative damage may occur in cisplatin-induced nephrotoxicity as a consequence of decreased renal GSH levels and antioxidant enzyme activity with enhanced lipid peroxidation (Husain et al 1996Somani et al 1995). Administration of antioxidants has been shown to ameliorate cisplatin-induced nephro-and neurotoxicity in various species of animals (McGuiness et al 1978;Dobyan et al 1986;Zunino et al 1989;Hamers et al 1993;Babu et al 1995;Husain et al 1998). The mechanisms of protective effects of antioxidants against cisplatin-induced nephrotoxicity is still unknown.…”

mentioning

confidence: 99%

Dose‐Dependent Protection by Lipoic Acid against Cisplatin‐Induced Nephrotoxicity in Rats: Antioxidant Defense System

Somani¹,

Husain²,

Whitworth

et al. 2000

Pharmacology & Toxicology

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This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatininduced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/ kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.

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Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug

Cited by 149 publications

References 20 publications

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Protection against Cisplatin-Induced Toxicities byN-Acetylcysteine and Sodium Thiosulfate as Assessed at the Molecular, Cellular, and in Vivo Levels

Dose‐Dependent Protection by Lipoic Acid against Cisplatin‐Induced Nephrotoxicity in Rats: Antioxidant Defense System

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