Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii

Abstract

Addition of paclitaxel (Taxol) at a concentration of 1 μM toToxoplasma gondii-infected human foreskin fibroblasts arrested parasite multiplication. Division of theT. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibition was irreversible, since the arrested intracellular form was incapable of leaving the host cell, infecting new cells, and initiating the growth of tachyzoites with normal morphology. Specifically, when paclitaxel was added to infected cells for 4 days and then removed by washing and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining T. gondii organisms with normal morphology. Syncytium-like structures in the cultures that were infected and treated with paclitaxel for 8 days were similar in appearance to those in preparations of infected paclitaxel-treated fibroblasts that had been cultured for 24 to 48 h. Pretreatment of the tachyzoites for 1 h with paclitaxel followed by the removal of the paclitaxel by repeatedly centrifuging and resuspending the parasites in fresh medium without paclitaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but did affect their subsequent ability to replicate within fibroblasts. Pretreatment of the fibroblasts with paclitaxel also diminished subsequent replication ofT. gondii in such host cells after 8 days. Thus, paclitaxel alters the ability of T. gondii to replicate in host cells. Inhibition of parasite microtubules by such compounds at concentrations which do not interfere with the function of host cell microtubules may be useful for development of novel medicines to treat T. gondii infections in the future.

In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells

“…At the maximum tolerated and recommended Phase II doses for PTX administered as a 6-h infusion, plasma levels have approached 10 M for 2-4 h, and have exceeded 1 M for 24 h, and 0.1 M for 48 h (Rowinsky et al, 1988). Besides, PTX did not alter the growth of fibroblasts at a concentration of 8.54 g/ml (Estes et al, 1998).…”

“…PTX has antineoplastic properties and is used to treat certain human malignancies (Rowinsky and Donerhower, 1995;Huizing et al, 1995). In vitro studies have shown that PTX inhibits the growth of the apicomplexan parasites P. falciparum and Toxoplasma gondii (Pouvelle et al, 1994;Estes et al, 1998).…”

Miniaturization and Validation of a Sensitive Multiparametric Cell-Based Assay for the Concomitant Detection of Microtubule-Destabilizing and Microtubule-Stabilizing Agents

“…[1][2][3][4][5][6][7][8][9][10][11][12] In addition to cancer, the microtubular cytoskeleton has been implicated in the etiology of a wide variety of diseases including neurodegenerative and mental diseases, [13][14][15] viral infections, [16][17][18] and parasitic diseases. [19][20][21][22][23][24] Therefore, pharmaceuticals that target microtubules may have wide clinical applications. Moreover, compounds targeting the microtubular cytoskeleton have proven to be valuable tools for basic research in cell biology.…”

Central nervous system toxoplasmosis in HIV pathogenesis, diagnosis, and therapy

“…Clinical trials have demonstrated that clarithromycin has synergistic activity with pyrimethamine in the effective treatment of toxoplasmosis [33]. Other drugs showing activity against Toxoplasma include atovaquone, artemisin, paclitaxel, trovafloxacin and quinupristin-dalfopristin [34][35][36][37][38][39].…”