Effects of BD-40, an ellipticine analogue (aza-ellipticine) on cell cycle traverse and DNA synthesis in cultures of synchronized mouse fibroblasts.

BD-40 is a pyrido-pyrrolo-isoquinoline analogue of ellipticine, which possesses oncostatic in vivo activity on experimental tumors, and dose-dependent cytostatic and cytotoxic activities on mammalian cells in culture. In order to appreciate the effects of the drug on the replication of DNA, cultures of murine fibroblasts were synchronized by thymidine double block, and BD-40 was added at the time of the block release. The drug did not interfere with the entry of cells in S phase, but a delay in S-phase transit was observed, regardless of the dose employed. In agreement with these data, DNA synthesis started at the same time in control cells and in BD-40 treated cells, but a significant reduction of 3H thymidine incorporation was found in drug-treated cells. This inhibition was not likely to result from a diminution of the specific activity of 3H-dTTP, since nuclei, isolated from cells previously incubated with the drug, also presented a strong diminution of synthetic activity in the presence of the four nucleoside triphosphate precursors (dNTPs). Analysis by alkaline sucrose gradient centrifugation of DNA synthesized in the presence of BD-40 showed that primary fragments, probably corresponding to the duplication of initial replicons, were normally formed but were not further elongated in cells treated with cytotoxic doses, while they were normally processed (although at a slower rate than in control) with a cytostatic drug concentration.(ABSTRACT TRUNCATED AT 250 WORDS)