The effects of topoisomerase II-reactive epipodophyllotoxins etoposide and teniposide as well as amsacrine on the viability of thymocytes in primary culture have been examined. All three drugs were shown to produce DNA cleavage detectable by resolving isolated DNA by pulsed field agarose gel electrophoresis. The DNA cleavage was found to have two components. The first was due to the interaction of the drugs with topoisomerase II, whereas the second component was due to endonuclease cleavage caused by the drug-induced entry of the thymocytes into pro grammed cell death or apoptosis. This second component of the DNA cleavage was also detected in thymocytes undergoing apoptosis following exposure to the glucocorticoid analogue, dexamethasone. The effect of the drugs on programmed cell death is dependent upon new protein and RNA synthesis, indicating that topoisomerase II has a role in the very first stages of the process. These results are discussed in terms of the use of this class of topoisomerase II-reactive drugs in chemotherapy. Drugs that interact with the enzyme topoisomerase II have been found to be particularly useful in the chemotherapeutic treatment of certain cancers. These include the epipodo phyllotoxins VP163 and VM26, as well as /M-AMSA which is an acridine derivative. All three drugs stabilize the DNA-topoisomerase II complex during strand passage preventing the resealing reaction from going to completion. DNA isolated from cells treated with the drugs contains covalently attached topoisomerase II subunits and strand breaks are de tectable when the protein is degraded. VM26 and VP 16 do not intercalate into DNA and appear to exert their effect, both in vivo and in vitro (using purified components), by binding di rectly, and specifically, to the enzyme molecule, whereas m-AMSA intercalates into DNA. However, although they are effective therapeutically, the mech anism by which these drugs kill cells is still controversial. In general, the drugs are thought to kill proliferating cancer cells by inhibiting topoisomerase II and preventing the cells from either completing S phase or undergoing chromosome segregation at mitosis since these are two cellular processes that have an absolute requirement for the enzyme. In general, cytotoxicity correlates with drug-induced DNA cleavage and increases when the drugs are administered during these phases of the cell cycle. There are, however, many exceptions, and since other cellular processes are also dependent upon topoisomerase II activity, particularly those requiring a change in chromatin structure, the precise mechanism of cytotoxicity remains to be established.

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