5-FLUOROURACIL AND LEVAMISOLE EXACERBATE DEMYELINATION IN SUSCEPTIBLEMICE INFECTED WITH THEILERS VIRUS

A multifocal inflammatory leukoencephalopathy is associated with the a dministration of 5-fluorouracil (5-FU), a pyrimidine analogue, and lev amisole (LE), an immunomodulator, in patients receiving adjuvant thera py for colon cancer. Cerebral biopsy demonstrated features indistingui shable from multiple sclerosis. We tested whether administration of th ese agents directly resulted in inflammatory demyelination in mice or whether they exacerbated demyelination in a host predisposed to myelin injury. We used mice intracerebrally infected with Theiler's murine e ncephalomyelitis virus (TMEV) which serves as an excellent model for m ultiple sclerosis. Varying dosages of 5-FU (240 mu g-2.4 mg) and LE (4 0 mu g-1 mg) were administered alone or in combination on a fixed sche dule to 52 normal SJL mice and 61 Theiler's virus-infected mice (51 SJ L/J mice susceptible to demyelination; 10 C57BL10 mice resistant to de myelination). Controls included 6 noninfected SJL and 26 infected mice (16 susceptible; 10 resistant) treated with phosphate-buffered saline (PBS). Inflammation or demyelination was not detected in brains or sp inal cords of noninfected SJL mice treated with 5-FU and/or LE. TMEV-s usceptible SJL mice treated with LE alone or in combination with 5-FU demonstrated more extensive inflammation and demyelination at Day 45 t han mice treated with PBS. Demyelination was accelerated in infected a nimals treated with these agents at 45 days but at 70 days a significa nt difference in extent of demyelination was no longer appreciated bet ween treatment and control groups. Treatment with 5-FU and LE did not convert normally resistant TMEV-infected C57BL/10 mice to demyelinatio n. These experiments support the hypothesis that 5-FU and LE may exace rbate inflammatory demyelination in a susceptible host. (C) 1997 Acade mic Press.