Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats

The current study was designed to evaluate the toxicity and activity of Spartaject(TM) Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 μmol of intrathecal Spartaject(TM) Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 μmol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 μmol x 1,6.2 μmol x 4 and 4.1 μmol x 4, respectively, against D-456 MG. A single dose of 8.1 μmol of intrathecal Spartaject(TM) Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 μmol x 1), 52.3% (2.0 μmol x 4), and 23% (8.1 μmol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.