Parthenolide, a clinically useful agent and migraine prophylaxis principle from the medicinal plant, feverfew (Tanacetum parthenium), was tested on two tumor cell lines for its ability to inhibit cell growth. At concentrations above 5.0 microM and an exposure time of 24 h, parthenolide inhibited cell growth in an irreversible fashion. However, at lower concentrations, the effect was reversible; parthenolide acted in a cytostatic fashion over multiple cell generations for mouse fibrosarcoma (MN-11) and human lymphoma (TK6) cell lines. After 24 h exposure to 2.5 microM parthenolide, approx. 85% of cells were able to continue cell cycling on removal of the chemical, as demonstrated by labeling of S-phase cells with BrdU. In a clonogenic assay, colony formation was also unchanged by exposure to this concentration of parthenolide. No indication of cell synchronization could be found, as evidenced by the lack of appearance of a peak of mitotic figures when cells were examined at 1 h intervals for 10 h after drug removal. The mechanism of the reversible growth inhibition is uncertain.