Intrathecal ACNU ? a new therapeutic approach against malignant leptomeningeal tumors

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Abstract
Pharmacokinetics, toxicity and therapeutic efficacy of intrathecal ACNU, 3-((4-amino-2-methyl-5-pyrimidinyl)methyl)-1-(2-chloroethyl)-1-nitrosourea, were studied in rats to determine if it is a new and effective method for the treatment of malignant leptomeningeal tumors. Pharmacokinetics of intracisternally administered ACNU was studied by macroscopial autoradiography using 14C-labeled ACNU. It was demonstrated that intracisternally administered ACNU distributed in the subarachnoid space and subpial layer of the brain in high concentration and was rapidly eliminated into the systemic circulation. The diffusional transport of ACNU into the deeper part of the brain was limited. More than 3.0 mg/kg of intracisternal ACNU induced progressive loss of the weight of body in normal rats, and 80% of the rat given 6.0 mg/kg died. Increase of capillary permeability, neuronal loss and gliosis were observed in the marginal layer of the brain facing to the subarachnoid space in the rat given more than 3.0 mg/kg of ACNU. Systemic and local toxicity was not observed in the rat given less than 1.5 mg/kg. Therapeutic effect of intrathecal ACNU against leptomeningeal tumors was evaluated in the rat with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells. The median survival time of the rat treated with 1.5 mg/kg of intracisternal ACNU once on day 2 or on day 5 after tumor inoculation was significantly prolonged by 173%, and 214% at maximum, respectively, as compared with that of the untreated animal. These findings suggest that intrathecal ACNU may be of value for clinical trial against leptomeningeal tumors.