Comparison of five agents in protecting the cochlea against the ototoxic effects of cisplatin in the hamster.
The purpose of this investigation was to study the ameliorating effects of four agents on cisplatin-induced ototoxicity. Hamsters were given a series of five cisplatin injections either alone or in combination with sodium thiosulfate (STS), diethyldihydrothiocarbamate (DDTC), and S-2(3-aminopropylamino) ethylphosphorothioic acid (WR-2721), or fosfomycin. Ototoxicity was assessed anatomically by quantifying the extent of cochlear damage with the scanning electron microscope and physiologically with measures of the auditory brain stem response. When administered alone, cisplatin induced widespread loss of outer hair cells (OHCs) along much of the cochlea in the hamster, especially in the basal and middle turns, with an average survival of only 56% of the OHC population. In contrast, inner hair cells resisted cisplatin ototoxicity in the hamster. Thus the ameliorative effects of the different test agents were assessed by counting the number of surviving OHCs in each treatment group and comparing with cisplatin-treated controls. STS provided the most effective protection against the ototoxic effects of cisplatin, yielding 91% survival of OHCs. DDTC also reduced the ototoxic effects of cisplatin, yielding 68% survival of OHCs. Cotreatment with WR-2721 and fosfomycin yielded 45% and 52% OHC survival, respectively, and thus did not provide any chemoprotection. The results closely paralleled those based on auditory brain stem response recordings in that the magnitude of threshold shift was proportional to the amount of OHC loss; also, the amount of threshold shift at each frequency was in good agreement with the pattern of hair cell loss along the cochlear spiral. Thus both histologic and physiologic results suggest that STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy.
Kaltenbach
J A
JA
Department of Otolaryngology-Head and Neck Surgery, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Church
M W
MW
Blakley
B W
BW
McCaslin
D L
DL
Burgio
D L
DL
D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use; D001309:Auditory Threshold / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects*; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology; D006224:Cricetinae; D004050:Ditiocarb / Q000008:administration & dosage / Q000627:therapeutic use; D004338:Drug Combinations; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005578:Fosfomycin / Q000008:administration & dosage / Q000627:therapeutic use; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000648:ultrastructure; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000648:ultrastructure; D008647:Mesocricetus; D008855:Microscopy, Electron, Scanning; D009925:Organ of Corti / Q000187:drug effects / Q000648:ultrastructure; D012665:Semicircular Canals / Q000187:drug effects / Q000648:ultrastructure; D013885:Thiosulfates / Q000008:administration & dosage / Q000627:therapeutic use
D000931:Antidotes; D000970:Antineoplastic Agents; D000975:Antioxidants; D002614:Chelating Agents; D004338:Drug Combinations; D013885:Thiosulfates; D005578:Fosfomycin; D004050:Ditiocarb; C017717:sodium thiosulfate; D004999:Amifostine; D002945:Cisplatin