INTRATHECAL MELPHALAN THERAPY OF HUMAN NEOPLASTIC MENINGITIS IN ATHYMIC NUDE RATS

We report the activity and toxicity of intrathecal melphalan in the tr eatment of human neoplastic meningitis in the subarachnoid space of at hymic nude rats. Animals received injections via chronic indwelling su barachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomy osarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treate d with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4 .0, or 5.0 mM solution, with clinical and histological evidence of neu rotoxicity observed at the 4.0 and 5.0 m?I levels. Multiple-dose toxic ity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treat ment of TE-671 with a single dose of 2.0 mM intrathecal melphalan prod uced an increase in median survival of 442% compared with saline contr ols (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphala n with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the trea tment of TE-671 revealed increases in median survival of 50% for 1.0 m M, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations . Comparison of a single dose of 1 mw melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 375+% for each of the regimens. Intrathecal melpha lan may be an important new addition in the treatment of neoplastic me ningitis and is currently being evaluated clinically in a Phase 1 tria l.