Abstract
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/m2 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/m2), 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.
Footnotes
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This work was supported by a Veterans Administration Merit Review Grant and by Grant NS 33618 from the National Institute of Neurological Disorders and Stroke to E.A.N.
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Conflict of interest statement: Dr. Neuwelt, Dr. Muldoon, and the Oregon Health & Science University have significant financial interests in Adherex Technologies, Inc., a company that may have a commercial interest in the results of this research and technology. The potential conflict of interest has been reviewed, and a management plan approved by the Oregon Health & Science University Conflict of Interest in Research Committee has been implemented.
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doi:10.1124/jpet.105.087601.
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ABBREVIATIONS: CDDP, cisplatin, cis-diamminedichloroplatinum; ROS, reactive oxygen species; STS, sodium thiosulfate; NAC, N-acetylcysteine; BUN, blood urea nitrogen; CR, creatinine; ABR, auditory brainstem response(s); SCLC, small cell lung cancer; PARP, poly(ADP-ribose) polymerase.
- Received April 6, 2005.
- Accepted June 9, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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