Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage.
Cancer Res
; 44(12 Pt 1): 5857-60, 1984 Dec.
Article
em En
| MEDLINE
| ID: mdl-6094001
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.
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Base de dados:
MEDLINE
Assunto principal:
Podofilotoxina
/
DNA de Neoplasias
/
Leucemia L1210
/
DNA Topoisomerases Tipo II
Limite:
Animals
Idioma:
En
Ano de publicação:
1984
Tipo de documento:
Article