Intrathecal ACNU against experimental leptomeningeal tumors

Therapeutic efficacy and cell kinetics of intrathecal ACNU, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea, were investigated in experimental meningeal carcinomatosis rats. Therapeutic effect of intrathecal ACNU (IT ACNU) against meningeal carcinomatosis model was evaluated in rats induced by intracisternal inoculation of Walker 256 carcinosarcoma cells. The median survival time of the rats treated with IT ACNU 1.5 mg/kg on day 5 after tumor inoculation was significantly increased by 145% as compared with that of non-treatment rats. The cell kinetics was studied immunohistochemically using indirect immunoperoxidase method with bromodeoxyuridine (BrdU) and anti-BrdU monoclonal antibody (Becton-Dickinson). The meningeal carcinomatosis rats were treated with IT ACNU (1.5 mg/kg) on the fifth day after tumor inoculation. Before and 12, 24, 48, 96 or 144 hours after treatment, the rats received intravenous BrdU (200 mg/kg) injection. Thirty minutes later, the rats were sacrificed and the brains were removed. Brain sections were stained immunohistochemically with anti-BrdU monoclonal antibody. Labeling index (LI) which represented the percentage of tumor cells in synthetic phase was obtained by counting immunoreactive cells under the microscope. Before treatment, LI was around 34% on day 5 after tumor inoculation and dropped to below 20% 12 to 48 hours after IT ACNU. However, it increased to around 36% on day 4 after IT ACNU. The antineoplastic effect of IT ACNU against meningeal carcinomatosis rats might be expected in the early stage of intrathecal administration.