Neoplastic meningitis can result from leptomeningeal dissemination of a variety of cancers. We now report the development of animal models of human neoplastic meningitis and activity of intrathecal 4-hydroperoxycyclophosphamide (4-HC) against the human rhabdomyosarcoma cell line 11 -671 and the human glioma cell line D-54 MG grown in the subarachnoid space of athymic rats. The injection of 5 x IO" II-67I or D-54 MG cells resulted in leptomeningeal tumor growth from the base of the brain to the cauda equina. Daily weights and neurological exami nations revealed progressive neurological deficits and weight loss, with death occurring between Days 21 and 27 for II,-671 and Days 14 and 26 for D-54 MG. 4-HC toxicity in non-tumor-bearing rats was assessed at dose levels of 2.0,10.0,15.0, and 20.0 HIM,with clinical and histolÃ3gica! evidence of neurotoxicity observed at the 2 highest dose levels. Intrathecal treatment with 4-HC on Day 8 following injection of TE-671 resulted in an increase in median survival of 20% (P = 0.04) at 1.0 IHM4-HC and 41% (P < 0.001) at 2.5 mivi4-HC. Intrathecal treatment with 4-HC (2.5 HIM)on Day 5 following injection of D-54 MG resulted in an increase in median survival of 23% (P = 0.009). These studies show the usefulness of the athymic rat model of human neoplastic meningitis and demonstrate the efficacy in vivo of intrathecally administered 4-HC against a human glioma and a human rhabdomyosarcoma cell line and the lack of toxicity at therapeutic levels of 4-HC in normal athymic rats.