Drug interaction effects on antitumour drugs (VIII): prevention of ifosfamide-induced urotoxicity by disulfiram and its effect on antitumour activity and acute toxicity of alkylating agents in mice.
To reduce the side-effects and to enhance the antitumour activities of antitumour agents, we have been investigating their combined use with routine drugs. In the present study, we examined the effects of disulfiram (DSF) in combination with ifosfamide (IFX). DSF prevented IFX-induced bladder damage in a dose-dependent manner in tumour-free ddY mice when orally administered simultaneously with antitumour agent, but failed to diminish the acute lethal toxicity or leukocytotoxicity of IFX. Diethyldithiocarbamate (DDTC) prevented IFX-induced bladder damage when administered simultaneously with IFX or 1 to 5 hr afterwards. The antitumour activity of IFX in ddY-mice inoculated with Sarcoma 180 or in C57BL/6J mice inoculated with EL-4 leukaemia was not impaired when it was given simultaneously with DSF or 3 hr before DDTC. Thus, neither DSF nor DDTC impaired the antitumour effect of IFX and both diminished its adverse effects. The bladder protection of DSF and DDTC appeared resulted from adduct formation with acrolein and not from inhibition of the metabolic activation of IFX.
Ishikawa
M
M
Department of Pharmacology and Toxicology, Tohoku College of Pharmacy, Sendai, Japan.
Takayanagi
Y
Y
Sasaki
K
K
D000818:Animals; D004221:Disulfiram / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007069:Ifosfamide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D001743:Urinary Bladder / Q000187:drug effects*
D004050:Ditiocarb; D004221:Disulfiram; D007069:Ifosfamide