Neurotoxicity of local administration of two nitrosoureas in malignant gliomas

The neurotoxicity of local administration of nitrosoureas in malignant gliomas was investigated clinicopathologically. Twenty patients were entered into this study: 13 were treated with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 7 with methyl 6-[3-(2-chloroethyl-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU). On the average, a single dose of 20 mg of ACNU was administered 15 times, for a total dose of 295 mg in each case, while a single dose of 11 mg of MCNU was given 2 times, for a total dose of 24 mg. These nitrosoureas provoked greater toxicity when the administration dose was larger or the indwelling multiperforated Silastic basket was in direct continuity with the ventricle or the basal cistern. Usually ACNU was well tolerated, whereas MCNU induced marked brain edema. Side effects consisted of headache, nuchal stiffness, vomiting, motor weakness, and cranial nerve palsy for ACNU, and headache, vomiting, abnormal respiration, and arrhythmia for MCNU. Pathological changes were represented by capsule formation, spongy degeneration and reactive gliosis of adjacent white matter, occlusion of neighboring arteries, and demyelination of cranial nerves in the patients treated with ACNU, while they were represented by focal brain necrosis in two patients treated with MCNU. The differences in neurotoxity of ACNU and MCNU conceivably derive from the different blood-brain delivery of these drugs.