Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy

In cancer chemotherapy with ifosfamide the occurrence of a drug-related encephalopathy represents a severe adverse-effect of unknown origin. We found that the underlying mechanism resides in the mitochondrial toxicity of ifosfamide metabolites. The electron accepting drug methylene blue can substitute for the demonstrated flavoprotein deficiency and its administration leads to resolution of the encephalopathy in patients. The prophylactic administration of methylene blue is equally effective via another principal mechanism, namely oxidation of the excessive quantity of NADH formed during ifosfamide metabolism. The inhibition by methylene blue of multiple amine oxidase activities also prevents formation of the neurotoxic chloroacetaldehyde from ifosfamide-derived chloroethyl amine. Thus, methylene blue exhibits several synergistic modes of actions which enable the dose-limiting neurotoxicity of alkylating chemotherapy with ifosfamide in cancer patients to be overcome.