peloruside-a and Disease-Models--Animal

We have shown previously that microtubule-stabilizing agents (MSA), a class of anti-proliferative compounds, can delay disease onset and reduce cumulative disease in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To explore how MSA could alter EAE disease processes, we compared the effect of administering MSA before or after peak antigen-specific proliferation and found that treatment before proliferation completely inhibited antigen-specific responses in the spleen; whereas administration of an MSA such as paclitaxel or docetaxel after peak proliferation did not. Despite the presence of antigen-specific responses in mice treated at the later time point, both treatment periods resulted in similar protection against EAE, suggesting that the protective effect of MSA in EAE could not be solely attributed to anti-proliferative activity. Instead, using in vivo migration assays, it was shown that MSA inhibit immune cell infiltration into the central nervous system (CNS). Furthermore, we found that the efficacy of an MSA could be enhanced by administering low doses of two different MSA together, such as peloruside A and ixabepilone, indicating that these MSA synergize in vivo to suppress disease. Taken together, these data suggest that MSA can suppress EAE by at least two distinct mechanisms of action--prevention of proliferation and inhibition of migration into the CNS. Finally, we have shown that a combination treatment with synergizing MSA may provide enhanced protection at lower therapeutic doses.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autoantigens; Bridged Bicyclo Compounds, Heterocyclic; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Disease Progression; Docetaxel; Drug Synergism; Encephalomyelitis, Autoimmune, Experimental; Epothilones; Growth Inhibitors; Humans; Lactones; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubules; Multiple Sclerosis; Paclitaxel; Taxoids