The inhibition by colchicine of the initiation of DNA synthesis by hepatocytes in regenerating rat liver and by cultivated WI-38 and C3H10T1/2 cells.

Abstract

AbstractColchicine inhibited the initiation of DNA synthesis by hepatocytes in vivo and by WI‐38 and C3H10T 1/2 cells in vitro. All three cell types were most sensitive to colchicine when it was administered at the time of, or shortly after, proliferative activation (by partial hepatectomy or medium‐serum change). WI‐38 and C3H10T 1/2 cells became less sensitive to colchincine as the time between proliferative activation and addition of the drug was increased. Hepatocytes, on the other hand, showed a second stage of sensitivity immediately before the onset of DNA synthesis. Ongoing DNA synthesis was not inhibited by colchicine in any of the cell types. The two prereplicative stages of colchicine sensitivity in liver were also sensitive to vincristine but not to lumicolchicine, an analogue of colchicine which does not bind to tubulin. The data obtained with these drugs indicates that microtubules may be involved in the prereplicative stages of cell proliferation, but non‐specific binding to other membrane proteins cannot be ruled out. Colchicine (at a dose of 50 μg/100 g of body weight), which when injected 30 minutes after hepatectomy delayed the initiation of DNA synthesis for at least 14 hours, delayed the induction of ornithine decarboxylase (at the beginning of prereplicative development) by only two hours. Thus, the inhibitory action of colchicine on the initiation of DNA synthesis does not appear to be mediated by inhibition of polyamine synthesis.