title: Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage.
abstract: Epipodophyllotoxins are an important new class of anticancer agents which include the compounds VM-26 (teniposide) and VP-16 (etoposide). The mechanism of action of these drugs appears to involve production of DNA single- and double-strand breaks by virtue of a temperature-sensitive interaction between drug and a heat-labile intranuclear component. We now report evidence indicating that type II topoisomerase is the likely intracellular target for the DNA strand-breaking effects of the epipodophyllotoxins. Both VM-26 and VP-16 stimulate site-specific DNA cleavage by a highly purified calf thymus type II topoisomerase. VM-26 is 5- to 10-fold more potent than VP-16 in this assay, a difference that is also seen when DNA strand breaks are assayed in isolated nuclei of mouse leukemia cells following drug exposure. Furthermore, a similar potency difference exists with respect to cytotoxicity. Equilibrium dialysis experiments using [3H]VP-16 indicate that the drug does not bind to DNA. Thus, we suggest that the epipodophyllotoxins exert their anti-cancer effects by "poisoning" type II topoisomerase without binding to DNA. In this regard, their actions may be analogous to those of nalidixic acid in bacteria.
mesh_terms: D000818:Animals; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D005047:Etoposide / Q000633:toxicity; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011034:Podophyllotoxin / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013713:Teniposide / Q000633:toxicity; D013950:Thymus Gland / Q000201:enzymology
chemical_list: D004273:DNA, Neoplasm; D005047:Etoposide; D013713:Teniposide; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin