Ultrastructural changes inducible with the plant alkaloid camptothecin.

The fine structural effects of camptothecin, a plant alkaloid with known antitumor activity, have been examined in ME-180 tissue culture cells. The drug has recently been shown to inhibit ribosomal RNA synthesis; nucleolar changes were therefore expected to occur. As shown here, camptothecin induces nucleoli to segregate but, in addition, it produces microspherules and perichromatin-type granules that are associated with the fibrillar nucleolar elements. Following removal of the latter structures by digestion, fibrils 100 to 160 A thick are observed at their place that, because of a close association with condensed chromatin, are suspected to be a dispersed form of chromatin. The fibrils, microsperules, and perichromatin-type granules accumulate around fibrillar centers where the fibrillar nucleolonemal strands are normally located. It appears that the fibrillar strands fail to develop, which may explain why transcription of the 45 S ribosomal RNA cannot take place. Camptothecin cannot induce the microspherules and the perichromatin-type granules in the presence of actinomycin D. Since template inactivation by actinomycin D prevents their formation, it is postulated that templates, under the action of camptothecin, are in an activated state, permitting these structures to develop, but precluding transcription of ribosomal RNA.