Pharmacokinetics, toxicity and therapeutic efficacy of intrathecal
ACNU, 3-[4-amino-2-methyl-5-pyrimidinyl)methyl)-1-(2-chloroethyl)-1-nitroso
urea, 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 macroscopical 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.