Salicylate protects hearing and kidney function from cisplatin toxicity without compromising its oncolytic action.
Salicylate has recently been demonstrated to protect against the auditory and vestibular side effects of aminoglycoside antibiotics. Similarities in the toxic mechanisms suggest salicylate as a treatment strategy to prevent the ototoxic side effects of cisplatin (CDDP). We first tested protection of the inner ear in Wistar rats receiving a single infusion of 16 mg CDDP/kg body weight with or without treatment with 100 mg/kg salicylate (bid) for 5 days beginning one day before the CDDP infusion. Cisplatin induced a threshold shift of more than 30 dB (at 14 kHz; measured by auditory evoked brain stem response) that was significantly reduced by salicylate. We then examined the protective potential of salicylate on the cochlea, peripheral nerves, and kidney in a rat model of breast cancer--Fisher344 rats implanted with highly metastatic MTLn3 breast cancer cells. Animals received 3 x 5 mg CDDP/kg (given every third day), and salicylate was administered at 100 mg/kg (bid) from 2 days before to 3 days after CDDP treatment. Salicylate significantly attenuated the CDDP-induced threshold shift from approximately 20 dB (at 16 and 24 kHz) to approximately 5 dB, and drastically reduced the loss of cochlear outer hair cells. Likewise, salicylate protected kidney function (measured as plasma blood urea nitrogen and creatinine levels) from CDDP toxicity. Protection of nerve conduction velocities of both sensory and motor nerves was minimal. The chemotherapeutic efficacy of CDDP on suppression of tumor mass and cancer cell metastasis remained unaffected by salicylate. The results suggest that administration of salicylate may become the basis of an effective therapeutic intervention against the ototoxic and nephrotoxic side effects associated with CDDP chemotherapy.
Li
Geming
G
Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, New York, USA.
Sha
Su-Hua
SH
Zotova
Elena
E
Arezzo
Joseph
J
Van de Water
Thomas
T
Schacht
Jochen
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001309:Auditory Threshold / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001943:Breast Neoplasms / Q000188:drug therapy; D002945:Cisplatin / Q000009:adverse effects*; D004336:Drug Antagonism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000648:ultrastructure; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000517:prevention & control*; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D012459:Salicylates; D002945:Cisplatin