Flow microfluorometric analysis of human lymphoid cells exposed in vitro to cytostatic concentrations of podophyllotoxin (0.01-5 #g/ml for 24 h) shows that a major part of this population (40-60%) has the DNA content of cells in the G~-M part of the cell cycle, and that approximately 60% of these cells are arrested in mitosis. Although a similar pattern of DNA distribution is seen in cultures exposed to cytostatic concentrations of VM-26 (0.01 ~tg/ml) and VP-16-213 (0.1 ug/ml), no mitotic cells are seen in these cultures. Exposure to higher concentrations of VM-26 (0.1 ~g/ml) and VP-16-213 (1.0 ~g/ml) inhibits cell cycle traverse, and after 24 h of exposure a major part of the population is arrested with the DNA content of cells in the S part of the cell cycle. Exposure to higher drug concentrations leads to a reduction in the number of cells with the late S-G2 DNA content.Whereas the cell cycle block induced by cytostatic concentrations of podophyllotoxin (0.01 t~g/ml) is readily reversible by reincubation of cells in drug-free medium, cells blocked by VM-26 and VP-16-213 are unable to resume cell-cycle traverse under similar conditions. Medicinal properties of root extracts fromPodophyllum sp. have been known for more than a century. However, interest in the possible pharmacological and cancer chemotherapeutic properties of the various podophyllin derivatives has been currently revived by observations that topical application of podophyllin will cure condyloma acuminatum (9). A number of active ingredients have been isolated from podophyllin and include podophyllotoxin and 4-demethyl podophyllotoxin (10). An excellent review of the biochemical, pharmacological, and clinical literature on podophyllin published up to the year 1954 has been compiled by Kelly and Hartwell (10).Some of the earlier cytological studies have shown the colchicine-like effect of podophyllotoxin on the mitotic and meiotic spindles of both plant and animal cells (22). In eggs, destruction of the mitotic and meiotic spindles by exposure to podophyllotoxin, picropodophyllotoxin, and podophyllic acid has been reported (3). A number of subsequent reports have confirmed these observations and also described podophyllotoxin-induced nuclear fragmentation and necrosis (10).
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