Effect of protective agents against cisplatin ototoxicity.
OBJECTIVE
The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat.


BACKGROUND
Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration.


METHODS
Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation).


RESULTS
Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested.


CONCLUSIONS
These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.
Department of Surgery and Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-1312, USA.
L P
LP
Rybak
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K
Husain
C
C
Morris
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C
Whitworth
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S
Somani
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000627:therapeutic use*; D001393:Azoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects*; D015834:Cochlear Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004050:Ditiocarb / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005978:Glutathione / Q000172:deficiency / Q000187:drug effects; D006311:Hearing Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D054833:Isoindoles; D015227:Lipid Peroxidation / Q000187:drug effects; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
C104409:4-methylthiobenzoic acid; D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D000975:Antioxidants; D001393:Azoles; D001565:Benzoates; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D004050:Ditiocarb; D005978:Glutathione; D002945:Cisplatin