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Altered Formation of DNA in Human Cells Treated with Inhibitors of DNA Topoisomerase II (Etoposide and Teniposide)¹

Radiumhemmet, Karolinska Hospital [U. L., S. L., U. N., G. W.], and Department of Histology, Karolinska Institutet [U. L., S. L.], P.O. Box 60500, S-104 01 Stockholm, Sweden

We have investigated the importance of DNA topoisomerase II for the formation of mammalian DNA replication intermediates. Treatment with the DNA topoisomerase II inhibitor etoposide (teniposide) prevents the formation of large intermediates, such as 10-kilobase DNA, but allows the formation of small intermediates, i.e., Okazaki fragments. In untreated cells, there is a distinct stage in which the 10-kilobase DNA intermediates are joined before the appearance of mature chromatin. We find that pretreatment with etoposide (teniposide) prevents the appearance of this stage. When the protocol is reversed and the cells contain labeled 10-kilobase DNA before exposure to the drugs, one can detect the stage.

¹ This work was supported by grants from the Swedish Cancer Society and the Karolinska Institutet.

² To whom requests for reprints should be addressed, at Radiumhemmet, Karolinska Hospital, P.O. Box 60500, S-104 01 Stockholm, Sweden.

Received 1/20/89. Revised 4/21/89. Revised 7/20/89. Accepted 8/10/89.