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Determinants Of Etoposide Cytotoxicity In Vitro

R. Lock
Published 1994 · Chemistry

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The epipodophyllotoxin etoposide, which has a broad range of antitumor activity (1,2), is used in combination chemotherapy regimens for the treatment of a variety of solid tumors, lymphomas and leukemias (3). Based almost exclusively on in vitro data, the mechanism of etoposide cytotoxicity has been defined to involve primarily the induction of protein-associated DNA strand breaks (cleavable complexes) via interaction with the nuclear enzyme, DNA topoisomerase II (topo II). These data are summarized as follows: Intracellular topo II levels and activity, or the expression of drug resistant forms of topo II, show a good correlation with the quantity of etoposide-induced DNA strand breaks and cytotoxicity in a variety of mammalian cell lines (4–8); etoposide inhibits the activity of topo II in vitro (9) and causes extensive DNA fragmentation in the presence of purified calf thymus topo II (10,11) with the enzyme attached to the 5′ phosphoryl end of the broken DNA strand (10); overexpression of plasmid-borne topo II in yeast leads to etoposide hypersensitivity (12).
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