Prevention of cisplatin-induced toxicity by selected dithiocarbamates.
Cisplatin (CDDP) is a widely used antineoplastic agent, the administration of which is associated with dose-related toxicities. Currently, ototoxicity is the dose-limiting toxicity of cisplatin and difficult to prevent. The purpose of this study was to determine the ability of two substituted dithiocarbamates, diethyldithiocarbamate (DDTC) and N-methyl-D-glucaminedithiocarbamate (NMGDTC) to abrogate cisplatin-induced toxicity in young female Hartley albino guinea pigs. The animals were divided into saline controls, CDDP only, NMGDTC only, and CDDP-DDTC or CDDP-NMGDTC combinations with DDTC or NMGDTC given 30 minutes before or 30 minutes after CDDP. Auditory brainstem responses (ABR) were recorded periodically in sound-attenuated rooms to assess hearing thresholds. Representative cochleas were harvested at autopsy, processed, and examined by scanning electron microscopy (SEM). The NMGDTC produced marked reduction of CDDP-induced ototoxicity and weight loss. No significant ABR shift was found regardless of the order of CDDP and NMGDTC administration, but the derivative was more effective in preventing anorexia and weight loss when given prior to CDDP. Specifically, groups of guinea pigs given NMGDTC prior to CDDP showed the only weight gain among the treatment groups. Diethyldithiocarbamate, the other dithiocarbamate evaluated in this study, did not provide protection from cisplatin ototoxicity regardless of the order of administration. A CDDP-induced weight loss was reduced when DDTC was administered prior to CDDP. In summary, NMGDTC given prior to CDDP offers remarkable protection against cisplatin-induced ototoxicity and weight loss. It may help eliminate dose-limiting cisplatin-induced toxicity and allow the use of cisplatin at higher doses in cancer chemotherapy.
Walker
E M
EM
Department of Pathology, Marshall University School of Medicine, Huntington, WV 25755.
Fazekas-May
M A
MA
Heard
K W
KW
Yee
S
S
Montague
D
D
Jones
M M
MM
D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004050:Ditiocarb / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D006168:Guinea Pigs; D006311:Hearing Disorders / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D008855:Microscopy, Electron, Scanning; D013012:Sorbitol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013113:Spin Labels; D013859:Thiocarbamates / Q000008:administration & dosage / Q000627:therapeutic use*; D015431:Weight Loss
D013113:Spin Labels; D013859:Thiocarbamates; D013012:Sorbitol; C041262:N-methyl-D-glucamine dithiocarbamate; D004050:Ditiocarb; D002945:Cisplatin