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F 11782 is a novel epipodophyllotoxin that targets eukaryotic topoisomerases and inhibits enzyme binding to DNA. While F 11782 has not been found to stabilize either topoisomerase I or topoisomerase II covalent complexes, drug treatment appears to result in DNA damage. F 11782 has also been shown to inhibit the DNA nucleotide excision repair (NER) pathway. Bisdioxopiperazine-resistant small cell lung cancer (SCLC) OC-NYH/Y165S and Chinese hamster ovary (CHO) CHO/159-1 cells having functional Y49F and Y165S mutations in the topoisomerase II α isoform were both resistant to F 11782. The catalytic activity of purified human Y50F and Y165S mutant topoisomerase II α (Y50F in the human protein corresponds to Y49F in the CHO protein) was likewise resistant to the inhibitory action of F 11782. F 11782 was also found to induce a non-covalent salt-stable complex of human topoisomerase II with DNA that was ATP-independent. F 11782 thus displays a dual mechanism of action on human topoisomerase II α, reducing its affinity for DNA while also stabilizing the protein bound in the form of a salt-stable complex. Our results suggest that topoisomerase II α is a target of F 11782 in vivo, and that F 11782 may act as a novel topoisomerase II poison.