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)