PACLITAXEL ARRESTS GROWTH OF INTRACELLULAR TOXOPLASMA-GONDII

Addition of paclitaxel (Taxol) at a concentration of 1 mu M to Toxopla sma gondii-infected human foreskin fibroblasts arrested parasite multi plication. Division of the T,gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts b y 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibiti on was irreversible, since the arrested intracellular form was incapab le of leaving the host cell, infecting new cells, and initiating the g rowth of tachyzoites with normal morphology, Specifically, when paclit axel was added to infected cells for 4 days and then removed by washin g and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining T,gondii organisms with normal morpholog y, Syncytium-like structures in the cultures that were infected and tr eated with paclitaxel for 8 days were similar in appearance to those i n preparations of infected paclitaxel-treated fibroblasts that had bee n cultured for 24 to 48 h, Pretreatment of the tachyzoites for 1 h wit h paclitaxel followed by the removal of the paclitaxel by repeatedly c entrifuging and resuspending the parasites in fresh medium without pac litaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but di d affect their subsequent ability to replicate within fibroblasts, Pre treatment of the fibroblasts with paclitaxel also diminished subsequen t replication of T, gondii in such host cells after 8 days. Thus, pacl itaxel alters the ability of T,gondii to replicate in host cells. Inhi bition of parasite microtubules by such compounds at concentrations wh ich do not interfere with the function of host cell microtubules may b e useful for development of novel medicines to treat T,gondii infectio ns in the future.