Amplification of oncogenes in human tumors has been associated with a poor prognosis. Microscopically visible amplified oncogenes can be located either within chromosomes in homogeneously staining regions, or in an extrachromosomal compartment in double minutes (DMs). The DMs are composed of submicroscopic circular DNA (episomes), which have multimerized to form the microscopically visible DMs. When amplified oncogenes are located in an extrachromosomal location, they are vulnerable to loss from the cell. In this study we have found that the topoisomerase II inhibitor etoposide, in concentrations easily achievable clinically, causes a significant decrease in the number of DM-containing amplified oncogenes in three different human tumor cell lines. The elimination of amplified oncogenes from the cell could be accompanied by less aggressive tumor behavior.